CN111808089B - Preparation method of drug eprogliflozin for treating diabetes or derivative thereof - Google Patents
Preparation method of drug eprogliflozin for treating diabetes or derivative thereof Download PDFInfo
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- CN111808089B CN111808089B CN201910287224.8A CN201910287224A CN111808089B CN 111808089 B CN111808089 B CN 111808089B CN 201910287224 A CN201910287224 A CN 201910287224A CN 111808089 B CN111808089 B CN 111808089B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 251
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 152
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 99
- 150000001875 compounds Chemical class 0.000 claims description 90
- 238000004440 column chromatography Methods 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 41
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 39
- 238000000746 purification Methods 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 23
- 238000000926 separation method Methods 0.000 claims description 22
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 21
- 239000003446 ligand Substances 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 17
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012044 organic layer Substances 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 238000004821 distillation Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
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- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 claims description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 146
- -1 aryl glycoside Chemical class 0.000 abstract description 58
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
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- 238000010561 standard procedure Methods 0.000 description 54
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- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 18
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
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- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
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- 125000000217 alkyl group Chemical group 0.000 description 9
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- 125000003118 aryl group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
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- 229910052736 halogen Inorganic materials 0.000 description 5
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- MZIVRTQIEKRAPI-UHFFFAOYSA-N methoxymethylsulfonylbenzene Chemical compound COCS(=O)(=O)C1=CC=CC=C1 MZIVRTQIEKRAPI-UHFFFAOYSA-N 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
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- 125000004429 atom Chemical group 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- 229910052717 sulfur Inorganic materials 0.000 description 1
- JWUBVPJWWYYRLJ-UHFFFAOYSA-N tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(B2OC(C)(C)C(C)(C)O2)C=N1 JWUBVPJWWYYRLJ-UHFFFAOYSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical group CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of drug eprogliflozin for treating diabetes or a derivative thereof. The invention utilizes alpha-O-alkenyl sulfone as electrophilic reagent to carry out Suzuki-Miyaura coupling reaction, the reaction raw material alpha-O-alkenyl sulfone has simple preparation and stable structure, and can overcome the defects of instability, difficult preparation and the like existing when organic halide and sulfonic acid are used as electrophilic reagent of Suzuki-Miyaura coupling reaction. Meanwhile, the reaction conditions of the reaction are mild, the heterocyclic ring and various functional groups can be compatible, the yield is high, and the large-scale process production can be realized. Meanwhile, the invention utilizes alpha-O-alkenyl sulfone as an electrophilic reagent to carry out Suzuki-Miyaura coupling reaction, can generate aryl glycoside and open-chain alkenyl ether with high yield, can also prepare type II diabetes drugs of eggliflozin and 2-deoxyeggliflozin, and has wide application.
Description
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a preparation method of a drug for treating diabetes mellitus, namely, epropanal or a derivative thereof.
Background
Suzuki-Miyaura coupling reaction, which is called Suzuki-Miyaura coupling reaction, has irreplaceable positions in organic synthesis and pharmaceutical chemistry, and can realize the construction of carbon-carbon bonds and synthesize a large amount of molecular frameworks. The obtained and stable organic boron reagent is used as an affinity reagent and plays a great role in the reactions. The most commonly used electrophilic reagents in the Suzuki-Miyaura coupling reaction are organic halides and sulfonic acid, and the compounds have the defects of low reactivity, instability, difficult preparation and the like, so that the development of alternative electrophilic reagents is very important.
Sulfones represent one of the basic functional groups in chemistry. The versatility and general stability of sulfones makes them important intermediates in many complex product synthesis schemes. However, the use of sulfones as electrophiles in cross-coupling reactions is relatively rare compared to organic halides or sulfonates, mainly for the following reasons: one is that oxidative insertion of the less polarized C — SO2R bond is considered more difficult; second, sulfones contain two C-SO2 bonds, which present selectivity problems in the oxidative insertion step; thirdly, during the oxidation insertion, the generated sulfinate (RSO 2-) is easy to remove sulfur dioxide to obtain R negative ions, and then a nucleophilic reagent rather than an electrophilic reagent enters the catalytic cycle again, so that the purpose is difficult to achieve. For example, the Yorimitsu group reports intramolecular desulfurization coupling of diaryl sulfones to yield diaryl groups.
Despite the above challenges, great progress has been made in using sulfones as electrophiles in cross-coupling. Interestingly, although vinyl or aryl sulfones have a longer history of use as C (sp 2) electrophiles, research in this area has been dormant since pioneering research by the Wenker and Julia topics. Most reported methods use grignard reagents as nucleophiles, which greatly limits their synthetic utility.
While the eprograzin or the derivative thereof is a medicine with better treatment effect on the type 2 diabetes mellitus, if a novel method for treating the eprograzin or the derivative thereof can be provided, the cost is low, and the yield is high, so that the method is good news for patients with the diabetes mellitus.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of an eprost drug for treating diabetes or a derivative thereof.
The invention provides a preparation method of drug of eggliflozin for treating diabetes or a derivative thereof, which comprises the following steps:
(1) Reacting alpha-O-alkenyl sulfone, an organic boron reagent, a ligand, alkali and a catalyst in a solvent to obtain a compound I;
(2) Reducing and substituting the compound I to obtain a coarse product of the eprost; or the compound I is reduced to obtain a crude product of the epropanal derivative;
(3) Purifying the crude product of the eprost or the crude product of the eprost derivative to obtain the eprost or the eprost derivative;
wherein the structural formula of the alpha-O-alkenyl sulfone is shown as a formula II:
in the formula II, the reaction solution is shown in the specification,
n is an integer of 0 to 4;
R 1 independently selected from substituted or unsubstituted C 1 ～C 6 Alkyl, -OR 3 Or any two of R 1 To form a substituted or unsubstituted 3-to 6-membered heterocyclic group; the substituent of the alkyl is halogen, nitryl, amino, hydroxyl, cyano-OR 3 (ii) a The substituent of the heterocyclic group is C 1 ～C 6 An alkyl group;
R 2 selected from substituted or unsubstituted aryl, substituted or unsubstituted 3-to 8-membered heterocyclyl; the substituent of the aryl or the heterocyclic group is C 1 ～C 6 Alkyl, halogen, C 1 ～C 6 Alkoxy, cyano, nitro, amino, hydroxy;
R 3 selected from benzyl, TBS groups, TIPS groups, substituted or unsubstituted 3-to 6-membered heterocyclic groups; the substituent of the heterocyclic group is substituted or unsubstituted C 1 ～C 6 Alkyl, -OR 4 (ii) a The substituent of the alkyl is halogen, hydroxyl, -OR 4 ；
R 4 Selected from benzyl, TBS groups, TIPS groups;
the organoboron reagent is
The structural formula of the compound I is
In the compound I, the reaction mixture is subjected to reaction,
n and R 1 The same as the alpha-O-alkenyl sulfone shown in the formula II.
Further, in the step (1), the molar ratio of the alpha-O-alkenyl sulfone, the organic boron reagent, the ligand, the base and the catalyst in the coupling reaction is 1-5; the molar volume ratio of the alpha-O-alkenyl sulfone to the solvent is 0.1-10 (mol/L);
preferably, the mole ratio of the alpha-O-alkenyl sulfone to the organoboron reagent to the ligand to the base to the catalyst in the coupling reaction is 1.5-2; the molar volume ratio of the alpha-O-alkenyl sulfone to the solvent is 0.1-0.. 2;
more preferably, the molar ratio of α -O-alkenyl sulfone, organoboron reagent, ligand, base, catalyst in the coupling reaction is 1; the molar volume ratio of the alpha-O-alkenyl sulfone to the solvent is 0.2.
Further, the air conditioner is provided with a fan,
in the formula II, the reaction mixture is shown in the formula II,
n is an integer of 2 to 3;
R 1 independently selected from substituted OR unsubstituted methyl, -OR 3 Or any two of R 1 To form a substituted 6-membered heterocyclic group; the substituent of the methyl is-OR 3 (ii) a The substituent of the heterocyclic group is C 4 An alkyl group;
R 2 selected from substituted or unsubstituted aryl, substituted or unsubstituted 6-membered heterocyclyl; the substituent of the aryl or heterocyclic group is C 1 ～C 3 Alkyl, halogen;
R 3 selected from benzyl, TBS groups, TIPS groups, substituted 6-membered heterocyclic groups; the substituent of the heterocyclic radical is substituted methyl alkyl, -OR 4 (ii) a The substituent of the alkyl is-OR 4 ；
R 4 Is selected from benzyl;
preferably, the α -O-alkenyl sulfone is of one of the following structural formulae:
more preferably, the α -O-alkenyl sulfone is of one of the following structural formulae:
further, in step (1), the ligand is selected from Ph 3 P or Cy 3 P·HBF 4 (ii) a The base is selected from KOH or NaOH; the catalyst is a Ni-containing catalyst; the solvent is tetrahydrofuran or tert-butyl alcohol;
preferably, in step (1), the ligand is Cy 3 P·HBF 4 (ii) a The alkali is KOH; the catalyst is Ni (COD) 2 (ii) a The solvent is tetrahydrofuran.
Further, in the step (1), the reaction temperature is 60-80 ℃; the reaction time is 8-16h; preferably, the reaction time is 12-16h.
Further, in the step (2), the compound I is reduced and substituted to obtain a crude product of the isegelizin, wherein the compound I is reduced to be dissolved in a solvent, cooled to 0 ℃, slowly added with a reducing agent and stirred for 10-15 hours; the substitution is a reduction of the product to which 3% H is added 2 O 2 Then adding 3M NaOH aqueous solution, and stirring at room temperature for 20-25 h; after the substitution, purifying the substituted product;
wherein the molar ratio of the compound I to the reducing agent is 1-5; the molar volume ratio of the compound I to the solvent is 0.1; compound I and 3% 2 O 2 The molar volume ratio of (1) to (5) is 0.1; the molar volume ratio of the compound I to the NaOH aqueous solution is 0.1;
preferably, in the step (2), the molar ratio of the compound I to the reducing agent is 1-3; the molar volume ratio of the compound I to the solvent is 0.1; compound I and 3% 2 O 2 The molar volume ratio of (a) to (b) is 0.1; the molar volume ratio of the compound I to the NaOH aqueous solution is 0.1 (mol/L).
Further, in the step (2), the compound I is reduced and substituted to obtain the ipragliflozin, the reduced compound I is dissolved in tetrahydrofuran, the temperature is cooled to 0 ℃, borane-tetrahydrofuran is slowly added, and the mixture is stirred for 12 hours; the substitution is a reduction of the product to which 30% H is added 2 O 2 Then adding 3M NaOH aqueous solution, and stirring at room temperature for 24h; the purification is that the product after the substitution is diluted by dichloromethane, washed, an organic layer is dried, filtered and distilled under reduced pressure,then the method is finished;
preferably, in step (2), the purification is a dilution of the substituted product with dichloromethane, which is then successively reduced with 20% NaHSO 3 Saturated NH 4 Washing with Cl, water and saturated brine, and washing the organic layer with anhydrous Na 2 SO 4 Drying, filtering, and distilling under reduced pressure.
Further, in the step (2), in the crude product of the israzin derivative obtained after the compound I is reduced, the compound I is dissolved in a solvent after the reduction, and the mixture is stirred and reacts for 20 to 30 hours in a hydrogen environment under the action of a catalyst; after the reduction, purifying the reduced product;
wherein the mass volume ratio of the compound I to the solvent is 1; the mass ratio of the compound I to the catalyst is 1.2-0.6;
preferably, in the step (2), the mass volume ratio of the compound I to the solvent is 1; the mass ratio of the compound I to the catalyst is 1.4-0.5.
Further, in the step (2), the solvent consists of ethyl acetate and methanol in a volume ratio of 5; the catalyst is 10% Pd/C; the stirring reaction time is 24 hours; the purification is carried out by filtering with diatomite and reduced pressure distillation.
Further, in the step (3), the purification is to dissolve the crude product in tetrahydrofuran, add tetrabutylammonium fluoride, stir at room temperature for 2h, perform reduced pressure distillation and column chromatography separation.
Further, the structural formula of the epropanal or the epropanal derivative is shown as a formula III:
preferably, the structure formula of the eprost or the eprost derivative is shown as the formula IIIA:
more preferably, the structure of the eprogliflozin or eproflozin derivative is as follows:
the compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or molecule.
The structures of the compounds in the invention are all structures capable of stably existing.
Substituent group of the invention "-C (O) R 7 The structural formula is
Substituent group' -OR of the invention 2 The structural formula is
Substituent group "-NR" of the present invention 5 R 6 "has a structural formula of>
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C) a ～C b ) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 8 Alkyl means a straight or branched chain alkyl group containing 1 to 8 carbon atoms; c 1 ～C 8 Alkoxy means an alkoxy group containing 1 to 8 carbon atoms.
In the present invention, the 3-to 6-membered heterocyclic group is a saturated or unsaturated monocyclic heterocyclic group consisting of 3 to 6 atoms, which carries at least one atom selected from O, S, or a substituted nitrogen atom, a silicon atom.
In the present invention, halogen is fluorine, chlorine, bromine or iodine.
In the present invention, the benzo 3-to 6-membered heterocyclic group means a 3-to 6-membered heterocyclic group on one benzene ring.
In the present invention, the abbreviations are those commonly used in the chemical arts, such as: TBS group is tert-butyldimethyl; the TIPS group is triisopropyl silicon group; bn is benzyl; t bu is butyl; ph is an aryl group; me is methyl; et is ethyl; boc is tert-butyloxycarbonyl; tol is tolyl.
The alpha-O alkenyl sulfone in the invention means that an oxygen is connected to the alpha position of the alkenyl sulfone, and the structural general formula is
Wherein R is 1 Is a substituent on the ring, n is the number of the substituent, R 2 Is a substituent on the sulfone group.
The invention takes the alpha-O-alkenyl sulfone as the electrophilic reagent, can effectively carry out Suzuki-Miyaura coupling reaction, does not have a plurality of problems existing when the sulfone participates in the Suzuki-Miyaura coupling reaction, has simple preparation and stable structure of the reaction raw material alpha-O-alkenyl sulfone, and can overcome the defects of instability, difficult preparation and the like existing when organic halide and sulfonic acid are used as the electrophilic reagent of the Suzuki-Miyaura coupling reaction. Meanwhile, the reaction conditions of the reaction are mild, the heterocyclic ring and various functional groups can be compatible, the yield is high, and the large-scale process production can be realized. Meanwhile, the invention utilizes alpha-O-alkenyl sulfone as an electrophilic reagent to carry out Suzuki-Miyaura coupling reaction, can generate aryl glycoside and open-chain alkenyl ether with high yield, can also prepare type II diabetes drugs of eggliflozin and 2-deoxyeggliflozin, and has wide application.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 preparation of an electrophile of the invention alpha-O-alkenylsulfone
1. Synthesis of 1-phenylsulfonyl-3, 4, 6-tribenzyloxy-D-glucal (8 a)
M-chloroperoxybenzoic acid (mCPBA, 2.5g,11.26mmol, 2.2equiv) was added in portions to a solution of SI-1 (3.24g, 5.12mmol,1.0 equiv) in Dichloromethane (DCM) at 0 ℃ and stirred at room temperature for 2 hours, followed by filtration with celite. Adding saturated NaHCO into the filtrate 3 And Na 2 S 2 O 3 The solution was stirred for 10min, extracted with dichloromethane and distilled under reduced pressure. Subsequent purification by chromatography column (petroleum ether/ethyl acetate =4 = 1) gave SI-2 (2.65g, 3.99mmol) in 78% yield.
Placing SI-2 (2.65g, 3.99mmol,1.0 equiv) in N 2 Dissolved in tetrahydrofuran (THF, 25 mL) under protective conditions, stirred at 0 deg.C, and then lithium bistrimethylsilyl amide (LiHMDS, 3.0mL, dissolved in n-hexane, at a concentration of 2.0M,1.5 equiv) was added dropwise thereto. Point plate monitoring, use saturated NH after reaction 4 The reaction was quenched with Cl solution, extracted with ethyl acetate and then distilled under reduced pressure. Purification on silica gel column (petroleum ether/ethyl acetate = 8). 1 H NMR(CDCl 3 ,400MHz)δ:7.95(d,J＝7.7Hz,2H),7.57(t,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,2H),7.36–7.24(m,11H),7.23–7.14(m,4H),6.22(d,J＝3.0Hz,1H),4.73(d,J＝11.3Hz,1H),4.68(d,J＝11.6Hz,1H),4.60(d,J＝11.3Hz,1H),4.56(d,J＝11.6Hz,1H),4.35(d,J＝12.0Hz,1H),4.31(d,J＝12.0Hz,1H),4.26(dd,J＝6.1,3.0Hz,1H),4.19(ddd,J＝8.1,4.6,3.1Hz,1H),3.85(dd,J＝8.1,6.0Hz,1H),3.71(dd,J＝11.5,4.6Hz,1H),and 3.66(dd,J＝11.5,3.1Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:152.61,138.07,138.04,137.81,137.49,133.96,129.11,128.73,128.65,128.51,128.39,128.12,127.97,127.94,127.68,127.53,105.80,79.89,74.87,73.86,73.41,71.45,and 67.61.IR(thin film,cm -1 ):3030,2866,1647,1448,1324,1160,1069,1026,734,725,696,685,and 613cm -1 .HRMS(DART-TOF)calculated for C 33 H 32 NaO 6 S + [M+Na] + m/z 579.1812, found 579.1821, melting point 75.5-79.6 ℃.
2. Synthesis of 1- (4-trifluoromethylphenylsulfonyl) -3,4, 6-tribenzyloxy-D-glucal (8 b)
SI-3 (2.34g, 6.0mmol, 1.0equiv) and 4- (trifluoromethyl) thiophenol (1.07g, 6.0mmol, 1.0equiv) were dissolved in 15ml of dichloromethane, and BF was slowly added under nitrogen protection at 0 deg.C 3 ·Et 2 O (2.34g, 6.0mmol,1.0 equiv). It was then stirred at room temperature for 8h with saturated NH 4 Quenching with Cl solution, washing with 0.3N NaOH solution, anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and silica gel column purification (petroleum ether/ethyl acetate = 4).
In N 2 Under the protection condition, the product obtained in the last step (1.37g, 2.7mmol, 1.0equiv) was dissolved in methanol, naOMe (58mg, 1.08mmol, 0.4equiv) was added and stirred at room temperature for 2 hours, and distillation was performed under reduced pressure. The spin-dried mixed system was dissolved in N, N-dimethylformamide (DMF, 18 mL), N 2 Adding NaH (864mg, 21.6mmol,8.0equiv, dispersed in mineral oil at a concentration of 60%) at 0 deg.C in portions under protection, stirring for 15min, and adding dropwise during 10minBnBr (3.69g, 21.6mmol,8.0 equiv), warmed to room temperature, stirred for 15h, quenched by pouring into ice-water, extracted with ethyl acetate (20mL. Times.3), anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and purification on silica gel column (petroleum ether/ethyl acetate = 10) gave SI-4 (1.61g, 2.3 mmol) in 85% yield.
Dissolving SI-4 (1.61g, 2.3mmol,1 equiv) in 15ml DCM, adding m-chloroperoxybenzoic acid (1.1g, 5.06mmol,2.2 equiv) in portions at 0 deg.C, stirring for 2h at room temperature, filtering, adding saturated NaHCO 3 The reaction was quenched in solution and Na was added 2 S 2 O 3 The solution was stirred for 10min. Subsequently, extraction with DCM and distillation of the organic layer under reduced pressure gave the product (1.43g, 1.9mmol) in 85% yield by purification of the crude product on a silica gel column (petroleum ether/ethyl acetate = 5.
The product obtained in the previous step was dissolved in 20ml THF at-78 ℃ and N 2 Lithium diisopropylamide (LDA, 1.8mL, dissolved in n-hexane, 2M,1.5 equiv) was added dropwise under protection, monitored by TLC plate at-78 deg.C and saturated NH 4 The reaction was quenched with Cl. The reaction was brought to room temperature, extracted with ethyl acetate, and the organic layer was distilled under reduced pressure and purified by silica gel chromatography (petroleum ether/ethyl acetate =7: 1) to give a pale yellow foamy solid 8b (1.16g, 1.9mmol) with a yield of 82%. 1 H NMR(CDCl 3 ,400MHz)δ:8.06(d,J＝8.2Hz,2H),7.69(d,J＝8.2Hz,2H),7.35–7.27(m,11H),7.22–7.16(m,4H),6.23(d,J＝3.1Hz,1H),4.73(d,J＝11.3Hz,1H),4.68(d,J＝11.6Hz,1H),4.60(d,J＝11.6Hz,1H),4.57(d,J＝11.6Hz,1H),4.39(d,J＝11.9Hz,1H),4.35(d,J＝11.9Hz,1H),4.26(dd,J＝5.9,3.1Hz,1H),4.22(ddd,J＝7.9,4.7,3.1Hz,1H),3.85(dd,J＝8.0,5.9Hz,1H),3.72(dd,J＝11.4,4.8Hz,1H),and 3.67(dd,J＝11.4,3.2Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.91,141.79,137.84,137.69,137.38,135.54(q,J＝33.1Hz),129.27,128.70,128.56,128.49,128.21,128.07,127.99,127.98,127.87,127.56,126.24(q,J＝3.7Hz),123.24(q,J＝273.7Hz),106.93,79.93,74.63,73.88,73.46,73.29,71.60,and 67.56. 19 F NMR(CDCl 3 ,376MHz)δ:–63.18.IR(thin film,cm -1 ):3029,3006,2989,2866,1320,1275,1261,1166,1131,1105,1060,1015,764,749,713,696,and 605cm -1 .HRMS(DART-TOF)calculated for C 34 H 31 F 3 NaO 6 S + [M+Na] + m/z 647.1686,found 647.1695.
3. Synthesis of 1-phenylsulfonyl-3, 4, 6-tri-tert-butyldimethylsilyloxy-D-glucal (15 a)
SI-3 (2.34g, 6.0mmol, 1.0equiv) and thiophenol (792mg, 7.2mmol, 1.2equiv) were dissolved in 15ml of dichloromethane, and N was added 2 And at 0 deg.C, adding BF slowly 3 ·Et 2 O (1.28g, 9.0mmol,1.5 equiv), stirring at room temperature for 8h to saturate NH 4 The Cl solution was quenched and washed with 0.3N aqueous NaOH. The organic layer was washed with anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, and purification on silica gel column (petroleum ether/ethyl acetate = 4).
At N 2 The product from the previous step (2.73g, 5.4mmol,1.0 equiv) was dissolved in methanol under protective conditions, naOMe (116mg, 2.16mmol,0.4 equiv) was added and stirred at room temperature for 2h, and distilled under reduced pressure. The resulting material was then dissolved in dichloromethane (30 mL), N 2 And at 0 deg.C, 2, 6-lutidine (5.78g, 54mmol,10.0 equiv) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 1.16g,43mmol,8.0 equiv) were added, stirred at room temperature for 8h, diluted with dichloromethane, extracted with saturated brine and dichloromethane (20mL. Times.3), anhydrous Na 2 SO 4 After drying, distillation under reduced pressure and silica gel chromatography (petroleum ether/ethyl acetate = 15) gave the TBS protected product SI-5 (3.74g, 5.1mmol, yield 95%).
Dissolving SI-5 (3.74g, 5.1mmol, 1equiv) in 30ml dichloromethane, adding m-chloroperoxybenzoic acid (mCPBA, 2.42g,11.2mmol, 2.2equiv) in batches at 0 ℃, stirring for 2h at room temperature, filtering with diatomite, adding saturated NaHCO into filtrate 3 And Na 2 S 2 O 3 The solution was stirred for 10 minutes, and the organic layer was distilled under reduced pressure. After spin-drying, the resulting mixture was dissolved in 20ml of tetrahydrofuranIn, N 2 And lithium diisopropylamide (LDA, 3.8mL, dissolved in n-hexane solution at a concentration of 2.0M,1.5 equiv) was added dropwise at-78 deg.C, monitored by TLC using saturated NH at-78 deg.C 4 Quenching with Cl solution, transferring the reaction solution to room temperature, extracting with ethyl acetate, and extracting with anhydrous Na 2 SO 4 After drying, the organic layer was distilled under reduced pressure and purified by means of a silica gel column to obtain 15a (2.37g, 3.8mmol) as a white solid in a yield of 74%. 1 H NMR(CDCl 3 ,400MHz)δ:7.95–7.90(m,2H),7.62–7.57(m,1H),7.52–7.46(m,2H),6.06(dd,J＝4.9,1.2Hz,1H),4.11(dddd,J＝6.9,5.2,3.2,1.6Hz,1H),4.03(ddd,J＝4.8,3.1,1.6Hz,1H),3.87(ddd,J＝4.4,3.2,1.2Hz,1H),3.74(dd,J＝11.2,5.6Hz,1H),3.69(dd,J＝11.2,6.6Hz,1H),0.88(d,J＝0.9Hz,9H),0.84(d,J＝0.9Hz,9H),0.73(d,J＝0.9Hz,9H),0.12(s,3H),0.10(s,3H),0.02(s,3H),0.00(s,3H),-0.01(s,3H),and-0.03(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:151.50,138.64,133.68,129.06,128.58,106.59,83.15,68.78,66.86,60.54,25.99,25.91,25.70,18.37,18.13,17.89,-4.21,-4.43,-4.46,-4.83,-5.25,and-5.38.IR(thin film,cm -1 ):3005,2954,2929,2888,2857,1275,1259,1076,833,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 30 H 56 NaO 6 SSi 3 + [M+Na] + m/z 651.2998, found 651.3001, melting point 103.4-105.6 deg.C.
4. Synthesis of 1-phenylsulfonyl-3-triisopropylsiloxy-4, 6-O-di-tert-butylsilyl-D-glucal (15 b)
Compound 15a (240mg, 0.84mmol,1.0 equiv) was dissolved in 20ml of THF, followed by addition of tetrabutylammonium fluoride (TBAF, dissolved in THF, concentration 1.0m,3.3ml,3.3 equiv), and the reaction solution was stirred for 2h under warm conditions, distilled under reduced pressure, and purified by a silica gel column (dichloromethane/methanol = 20) to obtain a white solid (260mg, 0.91mmol, yield 91%).
The product obtained in the previous step (240mg, 0.84mmol, 1.0equiv) was dissolved in 5ml of dry DCM, and pyridine (0.2ml, 2.52mmol, 3equiv) was addedThe reaction system was cooled to-35 ℃ under N 2 Dropwise adding under the protection condition ( t Bu) 2 Si(OTf) 2 (0.3 ml,0.9mmol, 1.08equiv), stirring was continued at-35 ℃ for 6h, using saturated NH 4 The reaction was quenched with Cl solution. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic layer was washed with anhydrous Na 2 SO 4 Drying, distillation under reduced pressure, silica gel column purification (petroleum ether/ethyl acetate = 3) gave a colorless oily product (354mg, 0.83mmol, yield 99%).
The product obtained in the previous step (354mg, 0.83mmol, 1.0equiv) was dissolved in dry DMF (5 ml), at-35 ℃ and N 2 Imidazole (141mg, 2.10mmol, 2.5equiv) and triisopropylchlorosilane (TIPSCl, 0.32ml,1.49mmol, 1.8equiv) were added dropwise under protection, and stirred at 35 ℃ for 6 hours to obtain saturated NH 4 The reaction solution is moved to room temperature, extracted by ethyl acetate, and the organic layer is anhydrous Na 2 SO 4 Drying and purification on silica gel column (petroleum ether/ethyl acetate = 3) gave 15b (435mg, 0.75mmol, yield 90%) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.95–7.89(m,2H),7.70–7.63(m,1H),7.60–7.52(m,2H),5.97(d,J＝2.3Hz,1H),4.51(dd,J＝7.0,2.4Hz,1H),4.15(dd,J＝10.0,4.4Hz,1H),3.98(dd,J＝16.0,10.8Hz,1H),3.96(dd,J＝16.4,10.0Hz,1H),3.87(ddd,J＝14.8,10.0,3.6Hz,1H),1.16–1.08(m,21H),1.03(s,9H),0.95and(s,9H). 13 C NMR(CDCl 3 ,101MHz)δ:151.40,138.04,134..14,129.28,,128.83,111.27,76.40,75.45,70.95,65.41,27.51,26.97,22.82,19.96,18.23,18.21,and 12.54.IR(thin film,cm -1 ):2941,2863,1649,1471,1331,1275,1260,1160,1130,1111,1065,1006,1076,826,765,and750cm -1 .HRMS(DART-TOF)calculated for C 29 H 50 NaO 6 SSi 2 + [M+Na] + m/z 605.2759, found605.2765, melting point 146.7.0-148.8 ℃.
5. Synthesis of alpha-O-alkenylsulfones of the invention (Compounds 15c-15 h)
The synthetic route of the alpha-O-alkenyl sulfone (15 c-15 h) of the invention is as follows:
wherein, the structural formulas of the corresponding sugar substrates SI-7 to SI-12 are respectively as follows:
the corresponding sugar substrate (1 eq) was placed in a round bottom flask and dried pyridine (sugar substrate concentration 0.3M) was added followed by acetic anhydride (10 eq). Stirring at room temperature for 15 hours until the reaction is completed. Quenching by adding water, extracting with ethyl acetate, washing with 1N hydrochloric acid for 3 times, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure. And separating by column chromatography to obtain the product.
Dissolving the product (1 equivalent) obtained from the upper reaction in dichloromethane (the product concentration is 0.3M), cooling to 0 ℃ under the protection of nitrogen, and sequentially adding thiophenol (1.2 equivalents) and BF 3 ·Et 2 O (1.5 eq). The reaction was carried out at room temperature for 8 hours, quenched with saturated ammonium chloride, extracted with dichloromethane, and washed with 0.3N sodium hydroxide and saturated brine in this order. Dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. And (4) separating the product by column chromatography.
Dissolving the product (1 equivalent) in DCM (product concentration 0.3M), cooling to 0 deg.C, adding M-chloroperoxybenzoic acid (2.2 equivalents) in portions, stirring at room temperature for 2 hr, filtering, and adding saturated NaHCO 3 The reaction was quenched in solution and Na was added 2 S 2 O 3 The solution was stirred for 10 minutes. Then extracted with DCM, the organic layer was distilled under reduced pressure and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5.
The product obtained in the previous step (1 eq) was dissolved in dry THF (0.1M concentration of product) at-78 ℃ and N 2 LDA (2.0M in n-hexane, 1.5 equivalents) was added dropwise under protection, monitored by TLC plate at-78 deg.C and saturated NH 4 The reaction was quenched with Cl. The reaction was brought to room temperature, extracted with ethyl acetate, the organic layer was distilled under reduced pressure and purified by silica gel chromatography (petroleum ether/ethyl acetate = 7) to give α -O-alkenylsulfoneThe product is 15c-15h.
(1) 1-phenylsulfone-3, 4, 6-tribenzyloxy-D-galactan (15 c)
1 H NMR(CDCl 3 ,400MHz)δ:7.89(br d,J＝8Hz,2H),7.53(br t,J＝8Hz,1H),7.39–7.25(m,13H),7.22–7.17(m,2H),7.17–7.12(m,2H),6.20(dd,J＝2.8,1.2Hz,1H),4.84(d,J＝11.6Hz,1H),4.69(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.52(d,J＝11.6Hz,1H),4.33–4.27(m,3H),4.25(d,J＝12.0Hz,1H),3.97(dt,J＝3.7,1.6Hz,1H),3.63(dd,J＝10.2,6.4Hz,1H),and3.54(dd,J＝10.2,6.4Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.44,138.25,138.18,137.82,137.68,133.68,128.99,128.62,128.46,128.33,128.32,128.01,127.84,127.74,127.67,127.65,127.58,107.14,78.69,73.59,73.43,71.58,71.52,70.46,and67.18.IR(thin film,cm -1 ):3028,3006,2989,2920,2865,1448,1324,1275,1260,1156,1100,1069,764,750,and 697cm -1 .HRMS(DART-TOF)calculated for C 32 H 32 NaO 6 S + [M+Na] + m/z 579.1812, found 579.1820, melting point 73.0-74.3 deg.C.
(2) 1-phenylsulfonyl-3, 4-dibenzyloxy-D-fucosylene (15D)
1 H NMR(CDCl 3 ,400MHz)δ:7.93–7.87(m,2H),7.57(t,J＝7.5Hz,1H),7.42(t,J＝7.7Hz,2H),7.37–7.25(m,8H),7.20–7.16(m,2H),6.19–6.16(m,1H),4.89(d,J＝12.0Hz,1H),4.74(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.57(d,J＝11.6Hz,1H),4.33(t,J＝3.2Hz,1H),4.26–4.19(m,1H),3.70–3.67(m,1H),and1.21(d,J＝6.8Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:151.74,138.39,138.32,137.77,133.62,128.96,128.63,128.30,128.26,128.01,127.69,127.60,106.42,76.38,73.72,72.90,72.40,71.48,and15.72.IR(thin film,cm -1 ):3028,3005,2989,1320,1275,1260,1151,1108,1059,764,750,718,697,686,and 618cm -1 .HRMS(DART-TOF)calculated for C 26 H 26 NaO 5 S + [M+Na] + m/z 473.1393,found 473.1401.
(3) 1-phenylsulfonyl-3, 4-dibenzyloxy-L-rhamnosene (15 e)
1 H NMR(CDCl 3 ,400MHz)δ:7.96–7.91(m,2H),7.66–7.61(m,1H),7.56–7.50(m,2H),7.37–7.23(m,10H),6.24–6.20(m,1H),4.78(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.58(d,J＝11.6Hz,1H),4.26(dd,J＝6.0,2.8Hz,1H),4.12–4.04(m,1H),3.49–3.43(m,1H),and1.29(d,J＝6.4Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:152.80,138.09,137.79,137.56,133.99,129.15,128.74,128.68,128.55,128.14,128.03,128.01,106.07,78.23,77.24,75.46,74.04,71.36,and16.89.IR(thin film,cm -1 ):3028,3005,2988,1446,1323,1275,1261,1159,1123,1060,764,750,724,697and 686cm -1 .HRMS(DART-TOF)calculated for C 26 H 26 NaO 5 S + [M+Na] + m/z 473.1393, found 473.1401, 62.8-64.4 deg.C
(4) 1-phenylsulfonyl-3, 4-dibenzyloxy-D-arabinoxene (15 f)
1 H NMR(CDCl 3 ,400MHz)δ:7.93–7.88(m,2H),7.65–7.59(m,1H),7.53–7.48(m,2H),7.35–7.23(m,10H),6.18(d,J＝4.8Hz,1H),4.70(s,2H),4.61(d,J＝12.0Hz,1H),4.54(d,J＝12.0Hz,1H),4.18(td,J＝4.2,3.6,1.0Hz,1H),4.11–4.05(m,2H),and3.72(ddd,J＝8.3,4.2,4.2Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:153.88,137.95,137.90,137.61,134.02,129.20,128.65,128.62,128.58,128.06,127.99,127.74,105.49,71.77,71.66,71.57,67.43,and66.10.IR(thin film,cm -1 ):3028,3005,2989,2870,1324,1275,1260,1163,1124,1074,764,750,and 698cm -1 .HRMS(DART-TOF)calculated for C 25 H 24 NaO 5 S + [M+Na] + m/z 459.1237, found 459.1238, melting point 105.8-107.3 deg.C
(5) 1-phenylsulfonyl-3, 4-dibenzyloxy-D-xylo-xene (15 g)
1 H NMR(CDCl 3 ,400MHz)δ:7.93(d,J＝7.8Hz,2H),7.62(t,J＝7.5Hz,1H),7.50(t,J＝7.7Hz,2H),7.38–7.25(m,8H),7.13(m,2H),6.24(d,J＝4.6Hz,1H),4.65(d,J＝12.0Hz,1H),4.56(d,J＝12.0Hz,1H),4.51(d,J＝12.0Hz,1H),4.48(d,J＝12.0Hz,1H),4.24(dd,J＝11.6,4.0Hz,1H),4.05–3.95(m,2H),and3.67(m,1H). 13 C NMR(CDCl 3 ,101MHz)δ:154.14,138.29,137.62,137.57,133.93,129.19,128.70,128.60,128.57,128.18,128.01,127.95,127.63,104.98,72.05,71.27,70.98,69.44,and66.52.IR(thin film,cm -1 ):3034,3006,2989,2870,1324,1275,1261,1161,1115,1076,764,749,and 698cm -1 ..HRMS(DART-TOF)calculated for C 25 H 24 NaO 5 S + [M+Na] + m/z 459.1237,found 459.1239.
(6) 1-phenylsulfonyl-hexabenzyloxy-D-malto-ene (15 h)
1 H NMR(CDCl 3 ,400MHz)δ:7.94–7.87(m,2H),7.43–7.35(m,3H),7.33–7.22(m,26H),7.17–7.09(m,4H),6.28–6.23(m,1H),5.22–5.16(m,1H),4.86(dd,J＝11.0,1.8Hz,1H),4.79–4.72(m,2H),4.67–4.59(m,2H),4.53(d,J＝4.5Hz,1H),4.50(d,J＝4.7Hz,1H),4.48–4.43(m,2H),4.41(d,J＝11.0Hz,1H),4.36–4.29(m,2H),4.29–4.24(m,1H),4.22–4.18(m,1H),4.12–4.08(m,1H),3.73(ddd,J＝9.2,5.1,2.0Hz,1H),3.67(ddd,J＝11.3,5.4,1.7Hz,1H),3.62(ddd,J＝11.3,5.4,1.7Hz,1H),3.60–3.57(m,2H),3.49–3.52(m,1H),3.49–3.46(m,1H),and3.37–3.32(m,1H). 13 C NMR(CDCl 3 ,101MHz)δ:152.68,138.84,138.44,138.19,138.03,137.96,137.93,137.36,133.95,129.14,128.65,128.59,128.55,128.46,128.42,128.38,128.34,128.06,128.00,127.95,127.91,127.87,127.76,127.75,127.65,127.57,104.83,97.02,81.80,79.82,79.54,77.45,75.67,75.08,73.50,73.38,73.22,72.84,71.00,70.66,70.51,68.13,and 67.07.IR(thin film,cm -1 ):3028,3006,2920,1453,1275,1260,1070,764,749,and 697cm -1 .HRMS(DART-TOF)calculated for C 60 H 60 NaO 11 S + [M+Na] + m/z 1011.3749,found 1011.3751. 1 H NMR(400MHz,Chloroform-d)δ3.73(ddd,J＝9.2,5.1,2.0Hz,1H),3.67(ddd,J＝11.3,5.4,1.7Hz,1H).
6. Synthesis of open-chain alpha-O-alkenylsulfone (Compound 19)
Methoxymethylphenylsulfone (18, 1.5 equiv) was dissolved in THF (15 mL), cooled to-78 ℃ under nitrogen, and LDA (9.0 mmol,3.0equiv, in n-hexane, 1.5M) was slowly added dropwise. After stirring for 15 minutes, diethyl chlorophosphate (4.5 mmol,1.5 equiv) was slowly added. The reaction was stirred for 1 hour, and a solution of the corresponding aldehyde (3.0 mmol,1.0 equiv) in THF (5 mL) was slowly added dropwise. Return to room temperature and stir overnight. Using saturated NH 4 And (3) quenching the Cl solution at low temperature, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure, and carrying out column chromatography separation to obtain a compound 19 which contains Z/E two configuration products and can be separated by column chromatography.
(1) Preparation of Compound 19a
Referring to standard procedures, benzaldehyde (3.0 mmol, 318mg) and methoxymethylphenylsulfone (3.3 mmol) were used as starting materials. Column chromatography was performed with petroleum ether/ethyl acetate =4 eluent to give compound 19a, e/Z =5, 771mg as a yellow oil, 94% yield.
(E) - (2-methoxy-2-phenylsulfonylvinyl) -benzene (E-19 a)
1 HNMR(CDCl 3 ,400MHz)(E-isomer)δ:8.01–7.95(m,2H),7.67–7.60(m,3H),7.58–7.52(m,2H),7.42–7.33(m,3H),7.23(s,1H),and3.87(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:153.33,139.11,133.73,131.55,130.00,129.96,129.26,129.00,128.50,122.68,and61.98.IR(thin film,cm -1 ):3005,2989,2942,2844,1446,1346,1304,1276,1260,1148,1094,1056,956,764,751,717,686,655,and 616cm -1 .HRMS(DART-TOF)calculated for C 15 H 14 NaO 3 S + [M+Na] + m/z 297.0556,found 297.0561.
(Z) - (2-methoxy-2-phenylsulfonylvinyl) -benzene (Z-19 a)
1 H NMR(CDCl 3 ,400MHz)(Z-isomer)δ:7.83–7.77(m,2H),7.61–7.56(m,1H),7.49–7.44(m,2H),7.35–7.29(m,5H),6.32(s,1H),and3.74(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:154.48,139.43,133.62,132.03,129.79,128.83,128.61,127.85,127.82,111.60,and58.37.IR(thin film,cm -1 ):3059,3023,2935,1626,1446,1322,1307,1233,1138,1081,974,916,751,729,687,and 627cm -1 .HRMS(DART-TOF)calculated for C 15 H 14 NaO 3 S + [M+Na] + m/z 297.0556,found 297.0556.
(2) Preparation of Compound 19b
Referring to standard procedure, 3-methylbutanal (3.0 mmol, 258mg) and methoxymethylphenylsulfone (3.3 mmol) were used as starting materials. Column chromatography was performed with petroleum ether/ethyl acetate =4, yielding compound 19b, e/Z =1.8, 602mg as colorless oil, 79% yield.
(E) - (1-methoxy-4-methyl-1-pentenyl) -sulphonylbenzene (E-19 b)
1 H NMR(CDCl 3 ,400MHz)(E-isomer)δ:7.94–7.88(m,2H),7.64–7.58(m,1H),7.56–7.50(m,2H),6.46(t,J＝7.8Hz,1H),3.80(s,3H),2.10(dd,J＝7.7,6.8Hz,2H),1.75(hept,J＝6.7Hz,1H),and0.92(d,J＝6.7Hz,6H). 13 C NMR(CDCl 3 ,101MHz)δ:154.08,139.27,133.50,129.09,128.21,126.18,63.11,34.46,28.12,and22.41.IR(thin film,cm -1 ):3070,2956,2870,1446,1322,1305,1160,1137,1092,1067,764,750,687,and 646cm -1 .HRMS(DART-TOF)calculated for C 13 H 18 NaO 3 S + [M+Na] + m/z 277.0869,found 277.0873.
(Z) - (1-methoxy-4-methyl-1-pentenyl) -sulphonylbenzene (Z-19 b)
1 H NMR(CDCl 3 ,400MHz)(Z-isomer)δ:7.97–7.90(m,2H),7.66–7.59(m,1H),7.57–7.50(m,2H),5.31(t,J＝8.0Hz,1H),3.59(s,3H),2.59(dd,J＝8.0,6.9Hz,2H),1.71(hept,J＝6.7Hz,1H),and0.95(d,J＝6.7Hz,6H). 13 C NMR(CDCl 3 ,101MHz)δ:152.97,140.05,133.60,129.00,128.20,114.83,58.77,33.91,29.39,and22.29.IR(thin film,cm -1 ):2956,2869,1635,1464,1447,1319,1307,1142,1121,1084,975,758,732,and 687cm -1 .HRMS(DART-TOF)calculated for C 13 H 18 NaO 3 S + [M+Na] + m/z 277.0869,found 277.0871.
(3) Preparation of Compound 19c
Referring to standard procedures, 4-triisopropylsilylbutyraldehyde (3.0 mmol, 733mg) and methoxymethylphenylsulfone (3.3 mmol) were used as starting materials. Column chromatography was performed with petroleum ether/ethyl acetate =15 eluent to give compound 19c, e/Z =1.1, 840mg, 68% yield as a colorless oil.
(E) - (1-methoxy-5-triisopropylsiloxy-1-pentenyl) -sulfone-benzene (E-19 c)
1 H NMR(CDCl 3 ,400MHz)(E-isomer)δ:7.95–7.87(m,2H),7.65–7.57(m,1H),7.56–7.48(m,2H),6.47(t,J＝7.7Hz,1H),3.82(s,3H),3.70(t,J＝6.1Hz,2H),2.34(q,J＝7.6Hz,2H),1.72–1.64(m,2H),1.12–1.06(m,3H),and1.04(d,J＝4.6Hz,18H). 13 C NMR(CDCl 3 ,101MHz)δ:153.93,139.24,133.52,129.11,128.33,126.92,63.23,62.43,31.87,22.37,18.08,and12.04.IR(thin film,cm -1 ):2941,2864,1318,1307,1275,1260,1156,1102,1063,881,764,750,723,and 685cm -1 .HRMS(DART-TOF)calculated for C 21 H 36 NaO 4 SSi + [M+Na] + m/z 435.1996,found 435.2001.
(Z) - (1-methoxy-5-triisopropylsiloxy-1-pentenyl) -sulfonyl benzene (Z-19 c)
1 H NMR(CDCl 3 ,400MHz)(Z-isomer)δ:7.97–7.89(m,2H),7.66–7.59(m,1H),7.55–7.49(m,2H),5.35(t,J＝8.0Hz,1H),3.75(t,J＝6.4Hz,2H),3.58(s,3H),2.76(q,J＝7.8Hz,2H),1.75–1.67(m,2H),1.13–1.08(m,3H),and1.07(d,J＝4.6Hz,18H). 13 C NMR(CDCl 3 ,101MHz)δ:152.67,140.09,133.60,129.04,128.16,115.33,62.88,58.61,33.55,22.14,18.15,and12.11.IR(thin film,cm -1 ):2940,2864,1447,1325,1275,1260,1144,1099,882,764,750,and 687cm -1 .HRMS(DART-TOF)calculated for C 21 H 36 NaO 4 SSi + [M+Na] + m/z 435.1996,found 435.2000.
(4) Preparation of Compound 19d
Referring to standard procedures, 4-triisopropylsilylbutyraldehyde (3.0 mmol, 463mg) and methoxymethylphenylsulfone (3.3 mmol) were used as starting materials. Column chromatography was performed with petroleum ether/ethyl acetate =15, yielding compound 19d, e/Z =1.9, 811mg as colorless oil, 84% yield.
(R, E) - (1-methoxy-4, 8-dimethyl-1, 7-nonadienyl) -sulphonylbenzene (E-19 d)
1 H NMR(CDCl 3 ,400MHz)(E-isomer)δ:7.96–7.86(m,2H),7.66–7.57(m,1H),7.56–7.48(m,2H),6.46(t,J＝7.7Hz,1H),5.04(tp,J＝6.9,1.2Hz,1H),3.81(s,3H),2.21(ddd,J＝14.5,7.5,5.8Hz,1H),2.13–2.04(m,1H),2.02–1.89(m,2H),1.67(s,3H),1.66–1.59(m,1H),1.58(s,3H),1.38–1.27(m,1H),1.25–1.13(m,1H),and0.90(d,J＝6.7Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:154.14,139.35,133.51,131.65,129.13,128.26,126.29,124.31,63.14,36.80,32.72,32.47,25.80,25.54,19.70,and17.73.IR(thin film,cm -1 ):3006,2961,2914,1446,1318,1305,1275,1260,1154,1065,764,750,687,and 645cm -1 .HRMS(DART-TOF)calculated for C 18 H 26 NaO 3 S + [M+Na] + m/z 345.1495,found 345.1499.
(R, Z) - (1-methoxy-4, 8-dimethyl-1, 7-nonadienyl) -sulphonylbenzene (Z-19 d)
1 H NMR(CDCl 3 ,400MHz)(Z-isomer)δ:7.97–7.90(m,2H),7.65–7.59(m,1H),7.56–7.50(m,2H),5.30(t,J＝8.0Hz,1H),5.12–5.05(m,1H),3.60(s,3H),2.68(ddd,J＝15.1,7.8,5.9Hz,1H),2.58(dt,J＝15.3,7.9Hz,1H),2.01(tp,J＝22.0,7.2Hz,2H),1.69(s,3H),1.60(s,3H),1.60–1.52(m,1H),1.39(dddd,J＝13.3,9.4,6.5,5.4Hz,1H),1.22(dddd,J＝13.6,9.3,7.9,6.0Hz,1H),and0.93(d,J＝6.7Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:153.02,140.07,133.59,131.48,129.00,128.22,124.64,114.92,58.82,36.72,33.71,32.22,25.82,25.66,19.44,and17.78.IR(thin film,cm -1 ):2962,2912,2850,1635,1447,1322,1307,1275,1260,1143,1084,974,763,750,and 688cm -1 .HRMS(DART-TOF)calculated for C 18 H 26 NaO 3 S + [M+Na] + m/z 345.1495,found 345.1498.
Example 2 Effect of different Process parameters on the Suzuki-Miyaura coupling reaction
1. Effect of ligands on Suzuki-Miyaura coupling reactions
The effect of different ligands on the Suzuki-Miyaura coupling reaction was investigated using the following reaction scheme as the basic reaction scheme.
The reaction results are shown in Table 1, in which the structural formulae of L1, L2, L3 and L4 are as follows:
TABLE 1 Effect of ligands on Suzuki-Miyaura coupling reactions
a Reaction conditions(unless otherwise specified)：8a(0.05mmol，1.0equiv)，9(0.10mmol，2.0equiv)，THF(0.4mL).Yield and conversion were determined by 1 H NMR using 1，3，5-trimethoxybenzene as internal standard. b Ni(cod) 2 instead of Ni(OTf) 2 .
From the results of table 1, it can be seen that: the ligand is Cy 3 P·HBF 4 (i.e., cy in Table 1) 3 PHBF 4 ) When the yield of the compound obtained is the highest, i.e. Cy 3 P·HBF 4 Is the most preferred ligand for this application.
2. Effect of solvent on Suzuki-Miyaura coupling reactions
The effect of different solvents on the Suzuki-Miyaura coupling reaction was investigated using the following reaction scheme as the basic reaction scheme.
The reaction results are shown in table 2:
TABLE 2 Effect of solvents on Suzuki-Miyaura coupling reactions
a Reaction conditions(unless otherwiise specified):8a(0.05mmol,1.0equiv),9(0.10mmol,2.0equiv),THF(0.4mL).Yield and conversion were determined by 1 H NMR using 1,3,5-trimethoxybenzene as internal standard.
As can be seen from table 2: tert-butanol and tetrahydrofuran facilitate the reaction. Among them, tetrahydrofuran is preferable.
3. Effect of the catalyst on the Suzuki-Miyaura coupling reaction
The following reaction scheme was used as a basic reaction scheme to study the effect of different catalysts on the Suzuki-Miyaura coupling reaction.
The reaction results are shown in table 3:
TABLE 3 Effect of different catalysts on Suzuki-Miyaura coupling reactions
a Reaction conditions(unless otherwise specified):8a(0.05mmol,1.0equiv),9(0.10mmol,2.0equiv),THF(0.4mL).Yield and conversion were determined by 1 H NMR using 1,3,5-trimethoxybenzene as internal standard. b Reactions were stirred at 80℃13h then 100℃10h.
As can be seen from Table 3:the Ni-containing catalyst is advantageous for the reaction to proceed as compared with other catalysts. Among them, the preferred catalyst is Ni (COD) 2 。
4. Effect of bases on Suzuki-Miyaura coupling reactions
The effect of different bases on the Suzuki-Miyaura coupling reaction was investigated using the following reaction scheme as the basic reaction scheme.
The reaction results are shown in table 4:
TABLE 4 Effect of different bases on Suzuki-Miyaura coupling reactions
a Reaction conditions(unless otherwise specified)：8a(0.05mmol，1.0 equiv)，9(0.10mmol，2.0equiv)，THF(0.4mL).Yield and conversion were determined by 1 H NMR using 1，3，5-trimethoxybenzene as internal standard.
As can be seen from Table 4: the most preferred base for this reaction is KOH.
5. Influence of temperature and time on Suzuki-Miyaura coupling reaction
The following reaction scheme was used as the basic reaction scheme to study the effect of different temperatures and times on the Suzuki-Miyaura coupling reaction.
The reaction results are shown in table 5:
TABLE 5 Effect of different temperatures and times on the Suzuki-Miyaura coupling reaction
a Reaction conditions(unless otherwise specified)：8a(0.05mmol，10 equiv)，9(0.10mmol，2.0 equiv)，THF(0.4mL)Yield and conversion were determined by1H NMR using 1，3，5-trimethoxybenzene as internal standard.
As can be seen from Table 5: the optimal temperature of the reaction is 60-80 ℃, and the reaction time is 8-16 hours.
The optimization of the reaction conditions shows that the optimal conditions for realizing the Suzuki-Miyaura coupling reaction by using the electrophilic reagent alpha-O alkenyl sulfone are as follows: the metal catalyst is Ni (COD) 2 The ligand is Cy 3 P·HBF 4 The solvent is tetrahydrofuran or tert-butyl alcohol, the alkali is KOH, the reaction temperature is 60-80 ℃, and the reaction time is 8-16h.
Example 3 preparation of aryl glycosides and open alkenyl ethers Using the alpha-O-alkenyl sulfones of the invention as electrophiles for Suzuki-Miyaura coupling reactions
The α -O-alkenyl sulfone prepared in example 1 (1 equivalent), the commercially available arylboronic acid or boronic ester (2 equivalents), cy 3 P·HBF 4 (0.2 eq.) was added to a screw-capped bottle containing a magnetic stirrer, and the cap was unscrewed and placed in a glove box. Adding Ni (COD) 2 (0.1 equiv.), KOH (2 equiv.), THF (0.2M, i.e., the concentration of α -O-alkenylsulfone in THF is 0.2M). After the small reaction bottle is screwed down, the glove box is moved out, and the bottle mouth is sealed by a black adhesive tape. The mixed system is stirred for 8 to 16 hours at the temperature of between 60 and 80 ℃. The reaction solution was then cooled to room temperature, diluted with ethyl acetate (10 ml) and saturated NH 4 After washing with Cl, it was extracted with ethyl acetate (10mL. Times.3). Anhydrous Na for organic layer 2 SO 4 Drying, distilling under reduced pressure, and purifying by a silica gel chromatographic column to obtain the target product. Wherein THF can be replaced by tert-butanol.
(1) 1-phenyl-3, 4, 6-tribenzyloxy-D-glucal (10)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), phenylboronic acid (0.40mmol, 48.8mg), ni (COD) according to the standard procedures 2 (0.02mmol，5.5mg)，Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg) and KOH (0.40mmol, 22.4 mg) in THF (1.0 mL) was stirred at 60 ℃ for 12 h. The column chromatography separation is carried out, eluent is petroleum ether/ethyl acetate =8:1, and the yellow oily compound 10 (92.6mg, 0.19mmol, yield is 94%) is obtained after separation and purification. 1 H NMR(CDCl 3 ，400MHz)δ：7.64-7.58(m，2H)，7.39-7.23(m，18H)，5.43(d，J＝3.2Hz，1H)，4.86(d，J＝11.2Hz，1H)，4.71(d，J＝11.6Hz，1H)，4.64(d，J＝11.6Hz，1H)，4.63(d，J＝12.4Hz，1H)，4.63(d，J＝11.6Hz，1H)，4.60(d，J＝12.4Hz，1H)，4.38(dd，J＝6.4，2.8Hz，1H)，4.26(ddd，J＝8.1，4.8，3.0Hz，1H)，3.98(dd，J＝8.4，6.0Hz，1H)，3.93(dd，J＝11.0，4.8Hz，1H)，and 3.88(dd，J＝10.9，3.0Hz，1H). 13 C NMR(CDCl 3 ，101MHz)δ：152.87，138.65，138.42，134.68，128.81，128.55，128.52，128.48，128.25，128.06，127.86，127.84，127.79，127.76，127.69，125.41，96.18，77.48，76.76，74.55，73.66，73.61，70.62，and68.77.IR(thin film，cm -1 )：3029，2930，2859，1652，1452，1276，1090，750，and 695cm -1 .HRMS(DART-TOF)calculated for C 33 H 32 NaO 4 + [M+Na]+m/z 515.2193，found 515.2187.
(2) 1-p-methoxyphenyl-3, 4, 6-tribenzyloxy-D-glucal (13 a)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-methoxyphenylboronic acid (0.40mmol, 60.8mg), ni (COD) according to the standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in THF (1.0 mL) was stirred at 60 ℃ for 12 h. Column chromatography was performed, and the eluent was petroleum ether/ethyl acetate =8, and separation and purification yielded compound 13a (85.7 mg,0.16mmol, yield 82%) as a colorless oily substance. 1 H NMR(CDCl 3 ,400MHz)δ:7.56–7.52(m,2H),7.36–7.25(m,15H),6.87–6.82(m,2H),5.31(d,J＝3.2Hz,1H),4.85(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.68(d,J＝11.6Hz,1H),4.64(d,J＝12.0Hz,1H),4.62(d,J＝11.6Hz,1H),4.60(d,J＝12.0Hz,1H),4.37(dd,J＝6.0,3.2Hz,1H),4.25(ddd,J＝8.0,4.8,2.8Hz,1H),3.96(dd,J＝8.4,6.0Hz,1H),3.92(dd,J＝11.0,4.9Hz,1H),3.87(dd,J＝10.9,3.0Hz,1H),and3.79(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:160.17,152.72,138.72,138.43,128.52,128.50,128.46,128.05,127.84,127.81,127.77,127.71,127.67,127.34,126.80,113.60,94.50,77.37,76.79,74.59,73.57,70.48,68.80,and55.38.IR(thin film,cm -1 ):3439,3028,3006,1599,1275,1259,1089,1070,1026,833,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 34 H 35 O 5 + [M+H] + m/z 523.2479,found 523.2485.
(3) 1-P-Dimethylaminophenyl-3, 4, 6-tribenzyloxy-D-glucal (13 b)
According to standard procedures, α -O-alkenyl sulfone 8a (0.20mmol, 111mg), pinacol ester of p-dimethylaminophenylboronic acid (0.40mmol, 98.9mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =8, to give compound 13b (79.3mg, 0.15mmol, 74% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.53–7.46(m,2H),7.37–7.24(m,15H),6.68–6.62(m,2H),5.26(d,J＝3.2Hz,1H),4.86(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.68(d,J＝10.4Hz,1H),4.66(d,J＝12.0Hz,1H),4.63(d,J＝10.4Hz,1H),4.61(d,J＝12.0Hz,1H),4.39(dd,J＝5.9,3.2Hz,1H),4.23(ddd,J＝8.1,4.7,3.1Hz,1H),3.95(dd,J＝10.8,4.8Hz,1H),3.95(dd,J＝11.2,3.2Hz,1H),and2.95(s,6H). 13 C NMR(CDCl 3 ,101MHz)δ:153.37,150.90,138.88,138.54,138.54,128.49,128.47,128.44,128.04,127.84,127.76,127.63,127.60,126.42,122.73,111.81,92.84,77.33,77.09,74.78,73.59,73.52,70.27,68.95,and40.50.IR(thin film,cm -1 ):3061,3028,2860,1609,1522,1359,1276,1260,1088,820,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 35 H 38 NO 4 + [M+H] + m/z 536.2795,found 536.2791.
(4) 1-p-fluorophenyl-3, 4, 6-tribenzyloxy-D-glucal (13 c)
According to standard procedures, α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-fluorophenylboronic acid (0.40mmol, 56.0mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, and the eluent was petroleum ether/ethyl acetate =8, and separation and purification yielded compound 13c (80.7 mg,0.16mmol, yield 79%) as a yellow oily substance. 1 H NMR(CDCl 3 ,400MHz)δ:7.59–7.54(m,2H),7.36–7.25(m,15H),7.04–6.96(m,2H),5.35(d,J＝3.2Hz,1H),4.85(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.36(dd,J＝5.6,3.2Hz,1H),4.26(ddd,J＝8.0,4.8,2.8Hz,1H),3.96(dd,J＝8.4,6.0Hz,1H),3.91(dd,J＝10.9,5.0Hz,1H),and3.86(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:163.19(d,J＝249.5Hz),151.99,138.58,138.32,130.86(d,J＝3.0Hz),128.56,128.53,128.49,128.06,127.88,127.85,127.79,127.74,127.32(d,J＝8.1Hz),115.26(d,J＝21.2Hz),95.94,77.43,76.53,74.43,73.62,73.58,70.70,and68.67. 19 F NMR(CDCl 3 ,376MHz)δ:–112.88.IR(thin film,cm -1 ):3461,3030,2864,1508,1275,1260,1228,1093,1027,839,764,749,and 697cm -1 .HRMS(DART-TOF)calculated for C 33 H 31 FNaO 4 + [M+Na] + m/z 533.2099,found 533.2104.
(5) 1-p-trifluoromethylphenyl-3, 4, 6-tribenzyloxy-D-glucal (13D)
According to standard procedures, the α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-trifluoromethylphenylboronic acid (0.40mmol, 76.0mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =8, to obtain compound 13d (83.0mg, 0.15mmol, 74% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.69(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),7.36–7.25(m,15H),5.50(d,J＝2.8Hz,1H),4.85(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.69(d,J＝11.6Hz,1H),4.64(d,J＝11.6Hz,1H),4.63(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.37(dd,J＝6.0,3.2Hz,1H),4.28(ddd,J＝8.0,4.8,2.8Hz,1H),3.98(dd,J＝8.4,6.0Hz,1H),3.92(dd,J＝10.9,4.9Hz,1H),and3.86(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.45,138.45,138.26,138.04,130.57(q,J＝32.5Hz),128.60,128.56,128.52,128.07,127.93,127.87,127.80,127.79,125.62,125.22(q,J＝3.8Hz),124.24(q,J＝272.7Hz),98.20,77.55,76.40,74.33,73.71,73.61,70.96,and68.56. 19 F NMR(CDCl 3 ,376MHz)δ:–62.55.IR(thin film,cm -1 ):3031,2864,1322,1164,1109,1066,1027,1014,848,732,and 695cm -1 .HRMS(DART-TOF)calculated for C 34 H 31 F 3 NaO 4 + [M+Na] + m/z 583.2067, found 583.2069, melting point 58.4-60.6 deg.C.
(6) 1- (3, 4-Dimethoxyphenyl) -3,4, 6-tribenzyloxy-D-glucal (13 e)
The α -O-alkenyl sulfone prepared in example 1, 8a (0.20mmol, 111mg), 3, 4-dimethoxyphenylboronic acid (0.40mmol, 72.8mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =8 as eluent to obtain compound 13e (90.6 mg,0.16mmol, 82% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.38–7.25(m,15H),7.19(dd,J＝8.4,2.0Hz,1H),7.11(d,J＝2.0Hz,1H),6.82(d,J＝8.4Hz,1H),5.31(d,J＝3.2Hz,1H),4.85(d,J＝11.6Hz,1H),4.72(d,J＝11.6Hz,1H),4.69(d,J＝11.2Hz,1H),4.65(d,J＝11.2Hz,1H),4.63(d,J＝12.4Hz,1H),4.62(d,J＝12.4Hz,1H),4.37(dd,J＝6.0,3.2Hz,1H),4.28(ddd,J＝8.4,4.8,3.2Hz,1H),3.96(dd,J＝7.6,4.8Hz,1H),3.92(dd,J＝10.8,5.2Hz,1H),3.88(dd,J＝10.8,3.2Hz,1H),3.87(s,3H),and3.85(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:152.64,149.70,148.67,138.72,138.41,138.36,128.53,128.52,128.45,128.06,127.85,127.83,127.73,127.70,127.68,118.33,110.78,108.76,94.92,77.36,76.66,74.58,73.55,73.53,70.65,68.78,56.02,and55.98.IR(thin film,cm -1 ):3464,3005,2863,1513,1453,1274,1261,1088,1070,1023,764,750,and 696cm -1 .HRMS(DART-TOF)calculated for C 35 H 37 O 6 + [M+H] + m/z 553.2585, found 553.2587, melting point 100.7-102.1 deg.C.
(7) 1-m-methylphenyl-3, 4, 6-tribenzyloxy-D-glucene (13 f)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), m-methylbenzeneboronic acid (0.40mmol, 54.4 mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =8, to obtain compound 13f as a white solid (76.0mg, 0.15mmol, yield 75%). 1 H NMR(CDCl 3 ,400MHz)δ:7.43–7.39(m,2H),7.37–7.25(m,15H),7.23–7.18(m,1H),7.13–7.09(m,1H),5.41(d,J＝2.8Hz,1H),4.85(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.69(d,J＝11.6Hz,1H),4.64(d,J＝12.0Hz,1H),4.62(d,J＝11.6Hz,1H),4.60(d,J＝12.0Hz,1H),4.38(dd,J＝6.0,3.2Hz,1H),4.25(ddd,J＝8.0,4.4,3.2Hz,1H),3.97(dd,J＝8.8,6.4Hz,1H),3.92(dd,J＝11.0,4.9Hz,1H),3.88(dd,J＝11.1,3.3Hz,1H),and2.34(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:153.00,138.68,138.42,137.77,134.61,129.57,128.52,128.49,128.45,128.14,128.03,127.83,127.81,127.76,127.72,127.66,126.08,122.58,96.03,77.43,76.77,74.56,73.60,73.53,70.53,68.73,and21.57.IR(thin film,cm -1 ):3028,2862,1453,1275,1261,1089,1026,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 34 H 34 NaO 4 + [M+Na] + m/z 529.2349, found 529.2350, melting point 43.5-46.6 deg.C.
(8) 1-o-fluorophenyl-3, 4, 6-tribenzyloxy-D-glucal (13 g)
According to standard procedures, α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), O-fluorophenylboronic acid (0.40mmol, 56.0mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =8 as eluent, and separation and purification yielded 13g of the compound as a white solid (73.5mg, 0.14mmol, yield 72%). 1 H NMR(CDCl 3 ,400MHz)δ:7.64(t,J＝7.6Hz,1H),7.39–7.23(m,16H),7.12(t,J＝7.6Hz,1H),7.05(dd,J＝11.6,8.4Hz,1H),5.62(d,J＝3.2Hz,1H),4.87(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.64(d,J＝12.0Hz,1H),4.62(d,J＝11.6Hz,1H),4.59(d,J＝12.0Hz,1H),4.41(dd,J＝6.4,2.4Hz,1H),4.24(ddd,J＝8.6,4.8,2.0Hz,1H),3.99(dd,J＝8.6,6.2Hz,1H),3.99(dd,J＝10.8,4.8Hz,1H),and 3.89(dd,J＝10.8,2.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:160.12(d,J＝252.5Hz),147.87(d,J＝4.0Hz),138.52,138.40,138.36,129.94(d,J＝9.1Hz),128.87(d,J＝3.0Hz),128.51,128.49,128.45,128.03,127.89,127.81,127.77,127.72,127.67,123.94(d,J＝3.0Hz),122.77(d,J＝11.1Hz),116.07(d,J＝23.2Hz),101.70(d,J＝11.1Hz),77.55,76.80,74.30,73.68,73.55,70.45,and68.70. 19 F NMR(CDCl 3 ,376MHz)δ:–112.84.IR(thin film,cm -1 ):3087,2918,2863,1492,1452,1091,1049,1026,732,and 695cm -1 .HRMS(DART-TOF)calculated for C 33 H 31 FNaO 4 + [M+Na] + m/z 533.2099, found 533.2101, melting point 59.1-62.3 ℃.
(9) 1- (1-naphthyl) -3,4, 6-tribenzyloxy-D-glucene (13 h)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), 1-naphthylboronic acid (0.40mmol, 68.8mg), ni (COD) according to the standard procedure 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =8, and separation and purification yielded compound 13h (97.6mg, 0.18mmol, yield 90%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:8.25(dd,J＝8.4,1.4Hz,1H),7.84–7.78(m,2H),7.54(dd,J＝7.2,1.4Hz,1H),7.46–7.38(m,3H),7.37–7.24(m,15H),5.22(d,J＝3.2Hz,1H),4.92(d,J＝11.2Hz,1H),4.77(d,J＝11.2Hz,1H),4.71(d,J＝12.0Hz,1H),4.63(d,J＝11.6Hz,1H),4.60(d,J＝12.0Hz,1H),4.56(d,J＝12.0Hz,1H),4.44(dd,J＝6.4,3.2Hz,1H),4.41(ddd,J＝8.0,4.8,2.4Hz,1H),4.13(dd,J＝8.4,6.4Hz,1H),3.99(dd,J＝10.8,4.8Hz,1H),and3.89(dd,J＝10.8,2.8Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:154.51,138.54,138.50,138.40,133.78,133.74,131.37,129.42,128.55,128.53,128.43,128.26,128.03,127.89,127.84,127.77,127.69,127.62,126.92,126.34,126.13,125.93,125.12,100.77,77.75,76.76,74.60,73.78,73.55,70.72,and68.81.IR(thin film,cm- 1 ):3028,3006,2861,1453,1275,1260,1071,1026,764,749,and 695cm- 1 .HRMS(DART-TOF)calculated for C 37 H 34 NaO 4 + [M+Na] + m/z565.2349,found 565.2358.
(10) 1-o-methylphenyl-3, 4, 6-tribenzyloxy-D-glucal (13 i)
alpha-O-alkenyl sulfone 8a (0.20mmol, 111mg), O-tolylboronic acid (0.40mmol, 54.4 mg), ni (COD) prepared in example 1 according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =8, to give compound 13i (81.1mg, 0.16mmol, yield 80%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.37–7.23(m,16H),7.22–7.18(m,1H),7.16–7.11(m,2H),5.01(d,J＝2.9Hz,1H),4.87(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.68(d,J＝11.6Hz,1H),4.61(d,J＝11.6Hz,1H),4.58(d,J＝12.0Hz,1H),4.53(d,J＝12.0Hz,1H),4.38(dd,J＝6.2,2.9Hz,1H),4.23(ddd,J＝8.8,4.8,2.6Hz,1H),4.01(dd,J＝8.8,6.2Hz,1H),3.91(dd,J＝10.8,4.8Hz,1H),3.84(dd,J＝10.8,2.7Hz,1H),and2.37(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:155.36,138.60,138.51,138.35,136.81,135.58,130.44,129.16,128.79,128.52,128.48,128.41,127.97,127.87,127.77,127.73,127.72,127.62,125.55,99.60,77.49,76.99,74.62,73.73,73.54,70.56,68.90,and20.37.IR(thin film,cm- 1 ):3006,2989,2862,1275,1260,1086,1041,1027,764,747,and 695cm- 1 .HRMS(DART-TOF)calculated for C 34 H 34 NaO 4 + [M+Na] + m/z 529.2349,found 529.2355.
(11) 1- (3, 4-methylenedioxyphenyl) -3,4, 6-tribenzyloxy-D-glucal (13 j)
Example 1 preparation according to standard proceduresa-O-alkenylsulfone of 8a (0.20mmol, 111mg), 3, 4-methylenedioxyphenylboronic acid (0.40mmol, 66.4 mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =8 as eluent, and isolation and purification yielded compound 13j (87.9mg, 0.16mmol, 82% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.36–7.27(m,15H),7.13(dd,J＝8.4,1.6Hz,1H),7.07(d,J＝1.6Hz,1H),6.75(d,J＝8.4Hz,1H),5.93(s,2H),5.28(d,J＝3.2Hz,1H),4.85(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.67(d,J＝11.6Hz,1H),4.63(d,J＝12.0Hz,1H),4.61(d,J＝11.6Hz,1H),4.59(d,J＝12.0Hz,1H),4.35(dd,J＝6.0,3.2Hz,1H),4.23(ddd,J＝8.0,4.8,3.2Hz,1H),3.95(dd,J＝8.4,6.0Hz,1H),3.90(dd,J＝10.9,4.9Hz,1H),and3.85(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:152.55,148.14,147.69,138.65,138.39,138.37,129.02,128.54,128.51,128.48,128.05,127.85,127.84,127.79,127.74,127.70,119.54,108.02,106.07,101.27,95.09,77.43,76.76,74.54,73.60,73.58,70.56,and68.71.IR(thin film,cm -1 ):3063,2867,1488,1444,1095,1037,1028,932,732,and 695cm -1 .HRMS(DART-TOF)calculated for C 34 H 32 NaO 6 + [M+Na] + m/z 559.2091, found 559.2095 melting point 52.2-55.4 ℃.
(12) 1-vinyl-3, 4, 6-tribenzyloxy-D-glucal ene (13 k)
According to standard procedures, the α -O-alkenyl sulfone 8a (0.20mmol, 111mg) prepared in example 1, vinyl boronic acid pinacol ester (0.40mmol, 61.6 mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and isolation and purification yielded compound 13k (42.4mg, 0.01mmol, 48% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.35–7.25(m,15H),6.07(dd,J＝17.2,10.8Hz,1H),5.63(dd,J＝17.2,1.6Hz,1H),5.16(dd,J＝10.8,1.7Hz,1H),4.92(d,J＝3.1Hz,1H),4.83(d,J＝11.4Hz,1H),4.68(d,J＝11.4Hz,1H),4.63(d,J＝11.6Hz,1H),4.61(d,J＝12.0Hz,1H),4.58(d,J＝12.0Hz,1H),4.56(d,J＝11.6Hz,1H),4.28(dd,J＝6.1,3.1Hz,1H),4.13(ddd,J＝8.1,4.7,3.0Hz,1H),3.90(dd,J＝8.6,6.1Hz,1H),3.86(dd,J＝11.0,4.8Hz,1H),3.82(dd,J＝11.0,3.1Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.71,138.54,138.47,138.40,131.36,128.53,128.51,128.47,128.07,127.85,127.76,127.67,115.64,100.98,77.21,76.65,74.54,73.74,73.60,70.63,68.72.IR(thin film,cm -1 ):3032,2917,2861,1689,1264,1228,1111,1097,908,729,and 697cm -1 .HRMS(DART-TOF)calculated for C 49 H 51 N 2 O 6 + [M+H] + m/z 763.3742,found 763.3745.
(13) 1-allyl-3, 4, 6-tribenzyloxy-D-glucal (13 l)
According to standard procedures, the α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), allylboronic acid pinacol ester (0.40mmol, 67.2mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluent petroleum ether/ethyl acetate =10, and 13l (77.6mg, 0.17mmol, yield 85%) of the compound was isolated and purified as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.44–7.23(m,15H),5.84(ddt,J＝16.9,10.1,6.8Hz,1H),5.18–5.00(m,2H),4.80(d,J＝11.5Hz,1H),4.70(d,J＝2.9Hz,1H),4.68–4.48(m,5H),4.20–4.13(m,1H),4.10(ddd,J＝8.1,5.0,3.1Hz,1H),3.84(dd,J＝8.1,5.8Hz,1H),3.81(dd,J＝10.9,5.0Hz,1H),3.75(dd,J＝10.8,3.0Hz,1H),2.84(d,J＝6.8Hz,2H). 13 C NMR(CDCl 3 ,101MHz)δ:154.71,138.64,138.42,138.39,133.84,128.48,128.44,128.02,127.82,127.80,127.78,127.67,117.25,95.71,77.07,76.10,74.36,73.54,73.49,70.44,68.71,and 38.06.IR(thin film,cm -1 ):3029,2864,1673,1453,1261,1095,1027,916,743,and 696cm -1 .HRMS(DART-TOF)calculated for C 30 H 32 NaO 4 + [M+Na] + m/z 479.2193,found 479.2196.
(14) 1-p-cyanophenyl-3, 4, 6-tribenzyloxy-D-glucene (13 m)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-cyanophenylboronic acid (0.40mmol, 58.8mg), ni (COD) according to the standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and separation and purification yielded 13m (72.5mg, 0.14mmol, yield 70%) as a white solid compound. 1 H NMR(CDCl 3 ,400MHz)δ:7.67(d,J＝8.0Hz,2H),7.59(d,J＝8.8Hz,2H),7.35–7.27(m,15H),5.53(d,J＝3.2Hz,1H),4.84(d,J＝11.2Hz,1H),4.70(d,J＝11.2Hz,1H),4.69(d,J＝11.6Hz,1H),4.64(d,J＝11.6Hz,1H),4.61(d,J＝12.0Hz,1H),4.58(d,J＝12.0Hz,1H),4.35(dd,J＝6.0,3.2Hz,1H),4.28(ddd,J＝8.0,4.8,2.8Hz,1H),3.97(dd,J＝8.4,6.0Hz,1H),3.91(dd,J＝10.9,5.0Hz,1H),and3.85(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:150.86,138.83,138.31,138.14,138.12,132.07,128.59,128.55,128.50,128.47,128.04,127.94,127.90,127.84,127.80,127.77,125.79,118.87,112.08,99.27,77.53,76.19,74.17,73.70,73.57,71.05,and68.43.IR(thin film,cm -1 ):3006,2989,2864,1275,1260,1097,764,749,and 698cm -1 .HRMS(DART-TOF)calculated for C 34 H 31 NNaO 4 + [M+Na] + m/z 540.2145, found 540.2146, melting point 103.5-106.6 deg.C.
(15) 1-p-methoxycarbonylphenyl-3, 4, 6-tribenzyloxy-D-glucal (13 n)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg) prepared in example 1, p-methoxycarbonylphenylboronic acid (0.40mmol, 72.0mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent to obtain compound 13n (89.1mg, 0.16mmol, 81% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:8.00(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.40–7.24(m,15H),5.53(d,J＝3.2Hz,1H),4.85(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.70(d,J＝11.6Hz,1H),4.64(d,J＝11.6Hz,1H),4.62(d,J＝12.4Hz,1H),4.59(d,J＝12.4Hz,1H),4.37(dd,J＝6.4,2.8Hz,1H),4.27(ddd,J＝8.4,4.8,3.2Hz,1H),3.98(dd,J＝8.4,6.0Hz,1H),3.87(dd,J＝10.6,4.8Hz,1H),3.90(s,3H),and 3.87(dd,J＝10.6,2.8Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:166.89,151.76,138.85,138.46,138.26,130.15,129.57,128.57,128.53,128.49,128.05,127.89,127.85,127.83,127.78,127.75,125.21,98.32,77.51,76.49,74.32,73.70,73.57,70.87,68.54,and52.22.IR(thin film,cm -1 ):3029,2862,1718,1274,1099,1026,1016,732,and 695cm -1 .HRMS(DART-TOF)calculated for C 35 H 34 NaO 6 + [M+Na] + m/z 573.2248, found 573.2249, melting point 65.9-68.1 ℃.
(16) 1- (4- (2-hydroxypropan-2-yl) phenyl) -3,4, 6-tribenzyloxy-D-glucal (13 o)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), 4- (2-hydroxypropan-2-yl) phenylboronic acid (0.40mmol, 72.0mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatographySeparation, eluent petroleum ether/ethyl acetate =10, and separation and purification yielded compound 13o as a colorless oil (78.2mg, 0.14mmol, yield 71%). 1 H NMR(CDCl 3 ,400MHz)δ:7.57(d,J＝8.4Hz,2H),7.44(d,J＝8.4Hz,2H),7.37–7.27(m,15H),5.41(d,J＝3.2Hz,1H),4.86(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.70(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.38(dd,J＝6.0,2.8Hz,1H),4.26(ddd,J＝8.4,4.8,3.2Hz,1H),3.97(dd,J＝8.4,6.0Hz,1H),3.92(dd,J＝10.9,4.8Hz,1H),3.88(dd,J＝11.0,3.1Hz,1H),1.82–1.74(br s,1H),and1.57(s,6H). 13 C NMR(CDCl 3 ,101MHz)δ:152.70,149.80,138.67,138.43,133.16,128.57,128.53,128.50,128.07,127.89,127.86,127.80,127.78,127.71,125.34,124.35,96.00,77.48,76.77,74.58,73.66,73.62,72.62,70.63,68.79,and31.83.IR(thin film,cm -1 ):3414,3030,2972,2865,1275,1261,1088,1071,1026,1015,748,733,and 696cm -1 .HRMS(DART-TOF)calculated for C 36 H 38 NaO 5 + [M+Na] + m/z 573.2611,found 573.2615.
(17) 1-p-acetylphenyl-3, 4, 6-tribenzyloxy-D-glucal ene (13 p)
According to standard procedures, the α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-acetylphenylboronic acid (0.40mmol, 65.6 mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, and the eluent was petroleum ether/ethyl acetate =10, to isolate and purify compound 13p (78.1mg, 0.15mmol, yield 73%) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.94–7.89(m,2H),7.71–7.66(m,2H),7.37–7.28(m,15H),5.55(d,J＝3.2Hz,1H),4.85(d,J＝11.2Hz,1H),4.72(d,J＝11.2Hz,1H),4.70(d,J＝11.6Hz,1H),4.66(d,J＝11.6Hz,1H),4.63(d,J＝12.4Hz,1H),4.60(d,J＝12.4Hz,1H),4.38(dd,J＝6.0,3.2Hz,1H),4.28(ddd,J＝8.4,4.8,3.2Hz,1H),3.98(dd,J＝8.4,6.0Hz,1H),3.92(dd,J＝10.9,4.9Hz,1H),3.88(dd,J＝10.9,3.0Hz,1H),and2.59(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:197.73,151.68,138.97,138.44,138.26,138.24,137.02,128.58,128.54,128.50,128.36,128.06,127.91,127.86,127.78,127.76,125.40,98.55,77.53,76.48,74.32,73.71,73.60,70.93,68.57,and26.76.IR(thin film,cm -1 ):3006,2989,2861,1680,1604,1275,1260,1089,1026,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 35 H 34 NaO 5 + [M+Na] + m/z 557.2298, found 557.2300, melting point 88.2-90.3 deg.C.
(18) 1-Paradimethylcarbamoylphenyl-3, 4, 6-tribenzyloxy-D-glucal (13 q)
According to standard procedures, the α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), p-dimethylcarbamoylphenylboronic acid (0.40mmol, 77.2mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give compound 13q (50.7mg, 0.09mmol, 45% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.63(d,J＝8.4Hz,2H),7.40–7.37(m,2H),7.36–7.26(m,15H),5.47(d,J＝3.2Hz,1H),4.86(d,J＝11.2Hz,1H),4.72(d,J＝11.2Hz,1H),4.69(d,J＝12.0Hz,1H),4.65(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.38(dd,J＝6.0,3.6Hz,1H),4.27(ddd,J＝8.4,4.8,3.2Hz,1H),3.98(dd,J＝8.4,6.0Hz,1H),3.92(dd,J＝10.9,4.9Hz,1H),3.87(dd,J＝10.9,3.0Hz,1H),3.10(s,3H),and2.95(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:171.38,152.01,138.50,138.29,138.29,136.45,135.77,128.55,128.51,128.47,128.04,127.86,127.84,127.80,127.77,127.72,127.13,125.29,97.19,77.48,76.57,74.41,73.67,73.58,70.78,68.64,39.64,and35.49.IR(thin film,cm -1 ):3006,2989,2862,1629,1275,1261,1079,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 36 H 37 NNaO 5 + [M+Na] + m/z 586.2564,found 586.2572.
(19) 1- (Dibenzothien-4-yl) -3,4, 6-tribenzyloxy-D-glucal ene (13 r)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), dibenzothiophene-4-boronic acid (0.40mmol, 91.2mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent to obtain compound 13r (99.3mg, 0.17mmol, 83% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:8.14–8.08(m,2H),7.82–7.76(m,1H),7.66(dd,J＝7.6,1.2Hz,1H),7.45–7.24(m,18H),5.61(d,J＝2.8Hz,1H),4.91(d,J＝11.6Hz,1H),4.76(d,J＝11.6Hz,1H),4.75(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.67(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.48(dd,J＝6.4,3.2Hz,1H),4.37(ddd,J＝8.8,6.4,3.2Hz,1H),4.11(dd,J＝8.6,6.4Hz,1H),4.04(dd,J＝11.2,4.0Hz,1H),and 4.01(dd,J＝11.2,4.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:152.91,140.32,138.63,138.45,138.40,137.12,136.61,135.11,130.12,128.57,128.52,128.45,128.07,127.93,127.85,127.78,127.65,126.90,125.23,124.43,124.33,122.44,122.03,121.56,99.23,77.97,77.10,74.56,73.86,73.69,70.64,and68.76.IR(thin film,cm -1 ):3028,3006,2859,1275,1260,1089,1041,1026,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 39 H 34 NaO 4 S + [M+Na] + m/z 621.2070, found 621.2079, melting point 75.6-78.1 deg.C.
(20) 1- (Thien-3-yl) -3,4, 6-tribenzyloxy-D-glucal ene (13 s)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), thiophene-3-boronic acid (0.40mmol, 51.2mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, and the eluent was petroleum ether/ethyl acetate =10, and separation and purification yielded compound 13s (89.8mg, 0.18mmol, yield 90%) as a yellow oily compound. 1 H NMR(CDCl 3 ,400MHz)δ:7.47(dd,J＝3.2,1.2Hz,1H),7.36–7.25(m,15H),7.24–7.21(m,1H),7.20–7.17(m,1H),5.30(d,J＝3.2Hz,1H),4.84(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.67(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.35(dd,J＝6.0,3.2Hz,1H),4.25(ddd,J＝8.2,4.8,3.2Hz,1H),3.95(dd,J＝8.4,6.0Hz,1H),3.90(dd,J＝10.9,4.9Hz,1H),and 3.85(dd,J＝11.0,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:149.52,138.62,138.37,138.35,136.88,128.53,128.51,128.47,128.05,127.84,127.76,127.74,127.69,125.70,124.99,122.36,95.87,77.30,76.41,74.39,73.60,73.56,70.60,and68.70.IR(thin film,cm -1 ):3434,3028,3006,2864,1275,1260,1087,1071,1026,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 31 H 30 NaO 4 S + [M+H] + m/z 521.1757,found 521.1765.
(21) 1- (benzofuran-5-yl) -3,4, 6-tribenzyloxy-D-glucal (13 t)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), benzofuran-5-boronic acid (0.40mmol, 64.8mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Performing column chromatography separation, wherein an eluent is petroleum ether/ethyl acetate =10, and performing separation and purification to obtain the compound of formula I13t (91.5mg, 0.17mmol, yield 86%) of a white solid compound was obtained. 1 H NMR(CDCl 3 ,400MHz)δ:7.86(d,J＝1.6Hz,1H),7.59(d,J＝2.0Hz,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.45–7.41(m,1H),7.37–7.26(m,15H),6.74(dd,J＝2.0,0.8Hz,1H),5.42(d,J＝3.2Hz,1H),4.87(d,J＝11.2Hz,1H),4.72(d,J＝11.2Hz,1H),4.71(d,J＝12.0Hz,1H),4.65(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.61(d,J＝12.0Hz,1H),4.40(dd,J＝6.0,3.2Hz,1H),4.30(ddd,J＝8.4,4.8,2.8Hz,1H),3.99(dd,J＝8.4,5.6Hz,1H),3.95(dd,J＝10.9,4.9Hz,1H),and 3.90(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:155.34,153.23,145.62,138.69,138.41,129.85,128.54,128.51,128.47,128.06,127.85,127.83,127.80,127.74,127.69,127.41,122.24,118.59,111.05,106.99,95.59,77.48,76.80,74.60,73.60,73.58,70.54,and68.79.IR(thin film,cm -1 ):3030,2865,1264,1110,1091,1027,730,and 696cm -1 .HRMS(DART-TOF)calculated for C 35 H 32 NaO 5 + [M+Na] + m/z 555.2142, found 555.2151, melting point 65.4-67.8 deg.C.
(22) 1- (benzofuran-3-yl) -3,4, 6-tribenzyloxy-D-glucal (13 u)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), benzofuran-3-boronic acid (0.40mmol, 64.8mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to obtain 13u (80.0mg, 0.15mmol, yield 75%) as a white solid compound by separation and purification. 1 H NMR(CDCl 3 ,400MHz)δ:7.83(s,1H),7.70–7.66(m,1H),7.49–7.45(m,1H),7.39–7.28(m,15H),7.28–7.21(m,2H),5.41(d,J＝2.8Hz,1H),4.88(d,J＝11.2Hz,1H),4.73(d,J＝11.2Hz,1H),4.71(d,J＝12.0Hz,1H),4.67(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.41(dd,J＝6.0,3.0Hz,1H),4.29(ddd,J＝8.2,4.8,2.8Hz,1H),4.00(dd,J＝8.4,6.0Hz,1H),3.93(dd,J＝10.9,5.1Hz,1H),and 3.87(dd,J＝10.9,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:155.74,147.50,143.84,138.72,138.36,138.32,128.61,128.55,128.51,128.08,127.91,127.89,127.82,127.75,124.81,124.64,123.19,121.22,117.02,111.79,97.64,77.29,76.72,74.50,73.71,73.60,70.83,and68.76.IR(thin film,cm -1 ):3028,3006,2861,1665,1451,1275,1260,1095,1040,1026,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 35 H 32 NaO 5 + [M+Na] + m/z 555.2142, found 555.2147, melting point 63.2-65.9 deg.C.
(23) 1- (Dibenzofuran-4-yl) -3,4, 6-tribenzyloxy-D-glucal ene (13 v)
The α -O-alkenyl sulfone prepared in example 1, 8a (0.20mmol, 111mg), dibenzofuran-4-boronic acid (0.40mmol, 84.8mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent to give compound 13v (100.2mg, 0.17mmol, 86% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:7.96–7.91(m,1H),7.90–7.87(m,1H),7.84–7.79(m,1H),7.60–7.55(m,1H),7.48–7.41(m,3H),7.39–7.25(m,15H),6.34(d,J＝2.8Hz,1H),4.92(d,J＝11.6Hz,1H),4.80(d,J＝11.6Hz,1H),4.77(d,J＝11.6Hz,1H),4.74(d,J＝11.6Hz,1H),4.69(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.56(dd,J＝6.0,3.2Hz,1H),4.33(ddd,J＝8.4,4.4,3.2Hz,1H),4.08(dd,J＝8.4,6.0Hz,1H),3.99(dd,J＝11.0,4.7Hz,1H),and 3.94(dd,J＝11.1,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:156.07,152.83,148.38,138.75,138.48,138.45,128.56,128.53,128.49,128.11,128.00,127.84,127.82,127.76,127.70,127.26,125.05,124.01,123.04,122.71,120.77,120.68,119.74,111.92,101.82,77.60,77.18,74.42,73.74,73.64,70.50,and68.86.IR(thin film,cm -1 ):3062,3029,2861,1450,1189,1086,1045,1026,746,732,and 695cm -1 .HRMS(DART-TOF)calculated for C 39 H 34 NaO 5 + [M+Na] + m/z 605.2298, found 605.2303, melting point 113.4-115.5 deg.C.
(24) 1-m-pyridine-3, 4, 6-tribenzyloxy-D-glucene (13 w)
The α -O-alkenyl sulfone 8a (0.20mmol, 111mg), 3-pyridineboronic acid (0.40mmol, 49.2mg), ni (COD) prepared in example 1 according to the standard procedure 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent to give compound 13w as a yellow oil (58.2mg, 0.12mmol, 59% yield). 1 H NMR(CDCl 3 ,400MHz)δ:8.84(d,J＝2.2Hz,1H),8.53(dd,J＝4.9,1.6Hz,1H),7.85(dt,J＝8.0,2.0Hz,1H),7.36–7.25(m,15H),7.25–7.22(m,1H),5.47(d,J＝3.2Hz,1H),4.85(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.65(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.36(dd,J＝5.9,3.2Hz,1H),4.28(ddd,J＝8.1,4.9,2.9Hz,1H),3.98(dd,J＝8.3,5.9Hz,1H),3.92(dd,J＝10.9,4.9Hz,1H),and 3.86(dd,J＝11.0,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:150.42,149.68,146.93,138.39,138.21,138.19,132.66,130.36,128.57,128.53,128.49,128.04,127.90,127.85,127.76,123.05,97.68,77.52,76.24,74.27,73.69,73.60,70.94,and68.50.IR(thin film,cm -1 ):3029,3006,2989,2862,1275,1260,1090,1043,1025,764,750,and 695cm -1 .HRMS(DART-TOF)calculated for C 32 H 32 NO 4 + [M+H] + m/z 494.2326,found 494.2325.
(25) 1- (quinolin-6-yl) -3,4, 6-tribenzyloxy-D-glucal ene (13 x)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), quinoline-6-boronic acid (0.40mmol, 69.2mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, and the eluent was petroleum ether/ethyl acetate =10, to obtain compound 13x (96.7mg, 0.18mmol, yield 89%) as a white solid by separation and purification. 1 H NMR(CDCl 3 ,400MHz)δ:8.87(dd,J＝4.0,1.6Hz,1H),8.11(dd,J＝8.4,1.6Hz,1H),8.07(d,J＝2.0Hz,1H),8.05(d,J＝8.8Hz,1H),7.90(dd,J＝9.2,2.0Hz,1H),7.39–7.25(m,16H),5.61(d,J＝3.2Hz,1H),4.87(d,J＝11.2Hz,1H),4.73(d,J＝11.2Hz,1H),4.70(d,J＝11.6Hz,1H),4.66(d,J＝11.6Hz,1H),4.65(d,J＝12.0Hz,1H),4.62(d,J＝12.0Hz,1H),4.42(dd,J＝5.9,3.2Hz,1H),4.34(ddd,J＝8.0,4.9,3.0Hz,1H),4.02(dd,J＝8.3,5.9Hz,1H),3.97(dd,J＝10.9,5.0Hz,1H),and3.92(dd,J＝10.9,3.1Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.90,150.68,148.47,138.49,138.28,138.26,136.59,132.50,129.26,128.55,128.51,128.47,128.03,127.86,127.84,127.80,127.76,127.72,126.74,124.41,121.53,97.74,77.49,76.48,74.41,73.62,73.53,70.80,and68.62.IR(thin film,cm -1 ):3031,2865,1264,1091,1027,764,731,and 697cm -1 .HRMS(DART-TOF)calculated for C 36 H 34 NO 4 + [M+H] + m/z 544.2482, found 544.2484, melting point 106.7-108.9 ℃.
(26) 1- (quinolin-3-yl) -3,4, 6-tribenzyloxy-D-glucal (13 y)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), quinoline-3-boronic acid (0.40mmol, 102.1mg), ni (COD) according to the standard procedure 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 (0.04mmol, 14.7 mg), and a solution of KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) were combinedThe mixture was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent to obtain compound 13y (94.5mg, 0.17mmol, 87% yield) as a white solid by separation and purification. 1 H NMR(CDCl 3 ,400MHz)δ:9.10(d,J＝2.4Hz,1H),8.33(d,J＝1.6Hz,1H),8.09(d,J＝8.4Hz,1H),7.80(dd,J＝8.0,1.3Hz,1H),7.68(ddd,J＝8.4,6.4,1.2Hz,1H),7.53(ddd,J＝8.4,6.4,1.2Hz,1H),7.40–7.25(m,15H),5.63(d,J＝3.2Hz,1H),4.88(d,J＝11.2Hz,1H),4.75(d,J＝11.6Hz,1H),4.72(d,J＝12.0Hz,1H),4.68(d,J＝11.6Hz,1H),4.64(d,J＝12.0Hz,1H),4.63(d,J＝12.0Hz,1H),4.41(dd,J＝6.0,3.2Hz,1H),4.35(ddd,J＝8.4,4.8,3.2Hz,1H),4.03(dd,J＝8.4,6.0Hz,1H),3.96(dd,J＝10.9,5.0Hz,1H),and3.91(dd,J＝10.9,3.0Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:150.41,147.96,147.89,138.40,138.20,132.08,129.78,129.29,128.59,128.53,128.49,128.38,128.05,127.90,127.88,127.88,127.77,127.77,127.54,127.39,127.05,98.14,77.53,76.28,74.31,73.68,73.58,71.04,and68.51.IR(thin film,cm -1 ):3029,2861,1650,1495,1452,1361,1291,1090,1025,788,748,733,and 695cm -1 .HRMS(DART-TOF)calculated for C 36 H 34 NO 4 + [M+H] + m/z 544.2482, found 544.2482, melting point 106.3-109.5 ℃.
(27) 1- (N-phenylindol-5-yl) -3,4, 6-tribenzyloxy-D-glucal (13 z)
According to standard procedures, α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), N-phenylindole-5-boronic acid (0.40mmol, 133.3mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and compound 13z (84.6mg, 0.14mmol, 68% yield) was isolated and purified as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.94(d,J＝1.6Hz,1H),7.43(dd,J＝8.7,1.7Hz,1H),7.39–7.23(m,18H),7.19(d,J＝8.7Hz,1H),7.09(d,J＝3.2Hz,1H),7.05(dd,J＝7.8,1.7Hz,2H),6.54(d,J＝3.1Hz,1H),5.39(d,J＝3.1Hz,1H),5.27(s,2H),4.87(d,J＝11.6Hz,1H),4.73(d,J＝11.6Hz,1H),4.70(d,J＝11.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.63(d,J＝11.6Hz,1H),4.62(d,J＝12.0Hz,1H),4.42(dd,J＝6.0,3.1Hz,1H),4.28(ddd,J＝8.1,4.7,3.0Hz,1H),4.00(dd,J＝8.5,6.0Hz,1H),3.96(dd,J＝11.0,4.9Hz,1H),and3.92(dd,J＝11.0,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:154.20,138.86,138.55,137.50,136.75,128.96,128.87,128.60,128.51,128.48,128.45,128.05,127.85,127.79,127.76,127.74,127.65,127.61,126.81,126.52,119.79,118.57,109.42,102.55,94.47,77.48,77.16,74.81,73.59,73.58,70.31,68.96,and50.27.IR(thin film,cm -1 ):3062,2920,2856,1648,1452,1094,1027,731,and 696cm -1 .HRMS(DART-TOF)calculated for C 42 H 40 NO 4 + [M+H] + m/z 622.2952,found 622.2956.
(28) 1- (1-phenyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) -3,4, 6-tribenzyloxy-D-glucal (13 aa)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), 1-phenyl-1H-pyrrolo [2,3-b ], according to standard procedures]Pyridine-5-boronic acid (0.40mmol, 133.7mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluent petroleum ether/ethyl acetate =10, and isolation and purification yielded compound 13aa (107.1mg, 0.17mmol, yield 86%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:8.62(d,J＝2.0Hz,1H),8.13(d,J＝2.1Hz,1H),7.38–7.23(m,18H),7.20–7.16(m,2H),7.15(d,J＝3.5Hz,1H),6.47(d,J＝3.5Hz,1H),5.47(s,2H),5.42(d,J＝3.2Hz,1H),4.87(d,J＝11.2Hz,1H),4.73(d,J＝11.2Hz,1H),4.70(d,J＝11.6Hz,1H),4.67(d,J＝11.6Hz,1H),4.64(d,J＝11.6Hz,1H),4.61(d,J＝11.6Hz,1H),4.41(dd,J＝6.0,3.2Hz,1H),4.31(ddd,J＝8.0,4.9,2.9Hz,1H),4.01(dd,J＝8.4,5.9Hz,1H),3.96(dd,J＝11.0,4.9Hz,1H),and3.90(dd,J＝11.0,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:152.33,147.98,141.39,138.64,138.41,138.38,137.77,128.81,128.70,128.56,128.52,128.48,128.06,127.89,127.84,127.80,127.76,127.73,127.69,127.53,126.17,123.37,119.85,100.81,95.39,77.53,76.74,74.59,73.65,73.63,70.62,68.78,and48.07.IR(thin film,cm -1 ):3029,2927,2862,1275,1261,1086,1026,906,764,749,729,and 695cm -1 .HRMS(DART-TOF)calculated for C 41 H 39 N 2 O 4 + [M+H] + m/z 623.2904,found 623.2911.
(29) 1- (5-methoxypyridin-3-yl) -3,4, 6-tribenzyloxy-D-glucal (13 ab)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), 5-methoxypyridine-3-boronic acid pinacol ester (0.40mmol, 61.2mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give 13ab (88.0 mg,0.17mmol, 84% yield) as a colorless oily compound. 1 H NMR(CDCl 3 ,400MHz)δ:8.45(d,J＝1.6Hz,1H),8.24(d,J＝2.8Hz,1H),7.37–7.36(m,1H),7.36–7.27(m,15H),5.47(d,J＝3.2Hz,1H),4.85(d,J＝11.2Hz,1H),4.72(d,J＝11.6Hz,1H),4.69(d,J＝12.0Hz,1H),4.65(d,J＝11.6Hz,1H),4.62(d,J＝12.4Hz,1H),4.58(d,J＝12.0Hz,1H),4.35(dd,J＝6.0,3.2Hz,1H),4.29(ddd,J＝8.4,4.8,2.8Hz,1H),3.97(dd,J＝8.4,6.0Hz,1H),3.91(dd,J＝10.9,5.0Hz,1H),3.86(dd,J＝10.9,3.0Hz,1H),and3.83(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:155.49,150.19,139.32,138.40,138.21,138.20,137.64,131.13,128.59,128.55,128.50,128.06,127.92,127.88,127.77,127.74,117.12,98.06,77.52,76.17,74.28,73.67,73.59,70.99,68.49,and55.70.IR(thin film,cm -1 ):3028,3006,2863,1453,1275,1260,1204,1089,1026,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 33 H 34 NO 5 + [M+H] + m/z 524.2431,found 524.2434.
(30) 1- (6-methoxypyridin-3-yl) -3,4, 6-tribenzyloxy-D-glucal (13 ac)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), 6-methoxypyridine-3-boronic acid pinacol ester (0.40mmol, 61.2mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and separation and purification yielded compound 13ac (94.3mg, 0.18mmol, yield 90%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:8.42(d,J＝2.4Hz,1H),7.74(dd,J＝8.7,2.5Hz,1H),7.36–7.26(m,15H),6.69(d,J＝8.7Hz,1H),5.30(d,J＝3.1Hz,1H),4.85(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.68(d,J＝11.6Hz,1H),4.64(d,J＝11.6Hz,1H),4.61(d,J＝12.4Hz,1H),4.58(d,J＝12.4Hz,1H),4.35(dd,J＝5.9,3.1Hz,1H),4.26(ddd,J＝8.0,4.9,2.9Hz,1H),3.96(dd,J＝8.4,6.0Hz,1H),3.94(s,3H),3.90(dd,J＝10.9,2.9Hz,1H),and3.85(dd,J＝10.9,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:164.44,150.84,144.37,138.53,138.31,138.29,135.88,128.58,128.54,128.50,128.08,127.89,127.88,127.82,127.79,127.74,123.99,110.30,95.52,77.47,76.46,74.41,73.67,73.66,70.78,68.65,and53.71.IR(thin film,cm -1 ):3029,2861,1601,1493,1453,1379,1284,1091,1023,831,748,733,and 696cm -1 .HRMS(DART-TOF)calculated for C 33 H 34 NO 5 + [M+H] + m/z 524.2431,found 524.2434.
(31) 1- (6-trifluoromethylpyridin-3-yl) -3,4, 6-Tribenzyloxy-D-glucene (13 ad)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), 6-trifluoromethylpyridine-3-boronic acid (0.40mmol, 76.4 mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and isolation and purification yielded compound 13ad (105.5mg, 0.19mmol, 94% yield) as a white solid. 1 H NMR(CDCl 3 ,400MHz)δ:8.90(d,J＝2.0Hz,1H),8.00(dd,J＝8.4,2.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.37–7.27(m,15H),5.55(d,J＝3.2Hz,1H),4.85(d,J＝11.6Hz,1H),4.72(d,J＝11.6Hz,1H),4.69(d,J＝12.0Hz,1H),4.65(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.35(dd,J＝6.0,3.2Hz,1H),4.31(ddd,J＝8.4,4.8,2.8Hz,1H),3.98(dd,J＝8.4,6.0Hz,1H),3.91(dd,J＝10.9,5.0Hz,1H),and3.85(dd,J＝10.9,2.9Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:149.09,147.75(q,J＝34.8Hz),146.99,138.22,138.08,133.82,133.09,128.65,128.59,128.54,128.07,128.00,127.91,127.86,127.80,121.64(q,J＝275.2Hz),120.00(q,J＝6.0Hz),99.83,77.65,75.96,74.09,73.77,73.65,71.31,and68.36. 19 F NMR(CDCl 3 ,376MHz)δ:–67.83.IR(thin film,cm -1 ):3029,3006,2989,2865,1334,1275,1260,1085,1025,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 33 H 31 F 3 NO 4 + [M+H] + m/z 562.2200, found 562.2208, melting point 73.2-75.1 ℃.
(32) 1- (6-Morpholinpyridin-3-yl) -3,4, 6-tribenzyloxy-D-glucene (13 ae)
The α -O-alkenyl sulfone prepared in example 1, 8a (0.20mmol, 111mg), 6-morpholinopyridine-3-boronic acid (0.40mmol, 83.2mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 (0.04mmol, 14.7 mg), and KOH (0.40mmol,22.4 mg) of tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and isolation and purification yielded compound 13ae (102.9mg, 0.18mmol, 89% yield) as a colorless oily substance. 1 H NMR(CDCl 3 ,400MHz)δ:8.45(d,J＝2.0Hz,1H),7.68(dd,J＝8.6,2.4Hz,1H),7.35–7.26(m,15H),6.56(d,J＝9.2Hz,1H),5.26(d,J＝3.2Hz,1H),4.85(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.67(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.61(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.36(dd,J＝6.0,3.2Hz,1H),4.24(ddd,J＝8.0,4.8,2.8Hz,1H),3.96(dd,J＝8.4,6.0Hz,1H),3.91(dd,J＝10.9,4.9Hz,1H),3.85(dd,J＝11.0,2.9Hz,1H),3.82–3.78(m,4H),and3.55–3.50(m,4H). 13 C NMR(CDCl 3 ,101MHz)δ:159.46,151.28,145.51,138.62,138.36,134.72,128.55,128.52,128.48,128.07,127.86,127.77,127.70,120.60,105.89,94.19,77.38,76.62,74.52,73.66,73.61,70.64,68.74,66.80,and45.62.IR(thin film,cm -1 ):3449,3005,2856,1595,1496,1275,1260,1238,1112,1068,1026,942,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 36 H 39 N 2 O 5 + [M+H] + m/z 579.2853,found 579.2862.
(33) 1- (6- (4-tert-Butoxycarbonylpiperazin-1-yl) pyridin-3-yl) -3,4, 6-tribenzyloxy-D-glucal (13 af)
According to standard procedures, α -O-alkenylsulfone 8a (0.20mmol, 111mg), 6- (4-tert-butoxycarbonylpiperazin-1-yl) pyridine-3-boronic acid pinacol ester (0.40mmol, 122.9mg), ni (COD) prepared in example 1 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and isolation and purification yielded compound 13af (108.4 mg,0.16mmol, 80% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:8.44(d,J＝2.4Hz,1H),7.67(dd,J＝8.9,2.4Hz,1H),7.39–7.26(m,15H),6.57(d,J＝8.9Hz,1H),5.26(d,J＝3.1Hz,1H),4.85(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.67(d,J＝11.6Hz,1H),4.63(d,J＝12.0Hz,1H),4.62(d,J＝11.6Hz,1H),4.59(d,J＝12.0Hz,1H),4.35(dd,J＝5.9,3.2Hz,1H),4.24(ddd,J＝8.0,4.9,3.0Hz,1H),3.95(dd,J＝8.3,5.8Hz,1H),3.91(dd,J＝11.0,4.9Hz,1H),3.85(dd,J＝11.0,3.0Hz,1H),3.58–3.50(m,8H),and1.48(s,9H). 13 C NMR(CDCl 3 ,101MHz)δ:159.12,154.91,151.26,145.52,143.75,138.60,138.34,134.76,128.53,128.51,128.46,128.05,127.85,127.75,127.68,120.39,106.11,94.13,80.09,77.36,76.60,74.51,73.64,73.59,70.62,68.72,45.08,28.55,and24.93.IR(thin film,cm -1 ):3461,2977,2861,1691,1594,1407,1364,1236,1164,996,931,749,733,and 697cm -1 .HRMS(DART-TOF)calculated for C 41 H 48 N 3 O 6 + [M+H] + m/z 678.3538,found 678.3544.
(34) 1- (2, 4-Dimethoxypyrimidin-5-yl) -3,4, 6-tribenzyloxy-D-glucal (13 ag)
The α -O-alkenylsulfone prepared in example 1, 8a (0.20mmol, 111mg), 2, 4-dimethoxypyrimidine-5-boronic acid (0.40mmol, 73.6 mg), ni (COD) according to the standard procedure 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give 13ag (79.5mg, 0.15mmol, 73% yield) as a colorless oily compound. 1 H NMR(CDCl 3 ,400MHz)δ:8.56(s,1H),7.36–7.25(m,15H),5.71(d,J＝3.2Hz,1H),4.86(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.67(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.61(d,J＝12.0Hz,1H),4.58(d,J＝12.0Hz,1H),4.38(dd,J＝6.4,3.2Hz,1H),4.20(ddd,J＝8.0,4.8,2.8Hz,1H),4.01(s,3H),4.00(s,3H),3.97(dd,J＝8.4,6.4Hz,1H),3.90(dd,J＝10.9,4.7Hz,1H)and3.84(dd,J＝11.0,2.8Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:167.83,164.47,157.36,146.42,138.59,138.32,138.23,128.49,128.47,128.04,127.85,127.83,127.74,127.71,109.95,101.07,77.41,76.97,74.23,73.69,73.62,70.62,68.63,54.99,and54.26.IR(thin film,cm -1 ):3006,2989,2864,1590,1556,1470,1400,1276,1260,1076,1011,803,764,749,and 696cm -1 .HRMS(DART-TOF)calculated for C 33 H 35 N 2 O 6 + [M+H] + m/z 555.2490,found 555.2491.
(35) 1- (11- (1-ethoxycarbonylpiperidin-4-ylalkenyl) -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridin-8-yl) -3,4, 6-tribenzyloxy-D-glucal (13 ah)
alpha-O-alkenyl sulfone 8a (0.20mmol, 111mg), 11- (1-ethoxycarbonylpiperidin-4-ylalkenyl) -6, 11-dihydro-5H-benzo [5,6] prepared in example 1 according to standard procedure]Cyclohepta [1,2-b ]]Pyridine-8-boronic acid (0.40mmol, 189.7 mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed with petroleum ether/ethyl acetate =10 as eluent, and isolation and purification gave compound 13ah (83.9mg, 0.11mmol, 55% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:8.39(dd,J＝4.8,1.7Hz,1H),7.44–7.38(m,3H),7.37–7.25(m,15H),7.16(d,J＝7.9Hz,1H),7.07(dd,J＝7.7,4.8Hz,1H),5.40(d,J＝3.1Hz,1H),4.84(d,J＝11.6Hz,1H),4.71(d,J＝11.6Hz,1H),4.68(d,J＝12.0Hz,1H),4.64(d,J＝12.0Hz,1H),4.62(d,J＝12.4Hz,1H),4.59(d,J＝12.4Hz,1H),4.34–4.39(m,1H),4.27–4.21(m,1H),4.13(q,J＝7.1Hz,2H),3.95(dd,J＝8.4,5.9Hz,1H),3.92–3.85(m,2H),3.84–3.74(m,2H),3.47–3.30(m,2H),3.19–3.09(m,2H),2.90–2.78(m,2H),2.55–2.45(m,1H),2.40–2.28(m,3H),and1.25(t,J＝7.1Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:157.42,157.31,155.62,152.61,152.56,146.68,139.94,139.84,138.63,138.39,138.37,137.64,137.59,137.53,137.11,135.13,133.80,133.71,129.27,129.21,128.52,128.48,128.44,127.99,127.81,127.73,127.66,126.04,126.02,123.20,123.17,122.23,96.09,96.04,77.42,76.65,76.61,74.53,73.57,73.53,70.56,70.53,68.74,61.39,44.98,32.04,32.01,31.91,31.85,30.90,30.66,and14.81.IR(thin film,cm -1 ):3032,2917,2861,1689,1264,1228,1111,1097,908,729,and 697cm -1 .HRMS(DART-TOF)calculated for C 49 H 51 N 2 O 6 + [M+H] + m/z 763.3742,found 763.3745.
(36) 1-phenyl-3, 4, 6-tri-tert-butyldimethylsilyloxy-D-glucal-ene (16 a)
alpha-O-alkenylsulfone prepared in example 1, 15a (0.15mmol, 94.3mg), phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluent petroleum ether/ethyl acetate =10, and separation and purification gave compound 16a (69.5mg, 0.12mmol, yield 82%) as a colorless oily substance. 1 H NMR(CDCl 3 ,400MHz)δ:7.65–7.61(m,2H),7.36–7.30(m,3H),5.28(d,J＝4.0Hz,1H),4.20–4.16(m,2H),4.00(dd,J＝11.2,7.0Hz,1H),3.92–3.85(m,2H),0.93(s,9H),0.91(s,9H),0.90(s,9H),0.15(s,6H),0.14(s,6H),0.06(s,3H),and0.03(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:150.81,135.72,128.50,128.18,125.44,98.16,80.67,70.52,69.17,61.78,26.15,26.10,26.06,18.53,18.30,18.27,-3.79,-3.89,-3.99,-4.49,-5.10,and-5.15.IR(thin film,cm -1 ):2954,2929,2886,2857,1472,1462,1256,1104,1081,833,772,and 750cm -1 .HRMS(DART-TOF)calculated for C 39 H 34 NaO 5 + [M+Na] + m/z 587.3379,found 587.3384.
(37) 1-phenyl-3-O-triisopropylsiloxy-4, 6-O-di-tert-butylsilyl-D-glucal (16 b)
alpha-O-alkenylsulfone prepared in example 1 (0.10mmol, 58.3mg), phenylboronic acid (0.20mmol, 24.4mg), ni (COD) according to standard procedures 2 (0.01mmol,2.8mg),Cy 3 PHBF 4 (0.02mmol, 7.4 mg), and a solution of KOH (0.20mmol, 11.2mg) in tetrahydrofuran (1.0 mL) were stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give compound 16b (31.2mg, 0.06mmol, 60% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.54–7.49(m,2H),7.35–7.29(m,3H),5.23(d,J＝2.3Hz,1H),4.59(dd,J＝6.7,2.4Hz,1H),4.32(dd,J＝10.4,4.8Hz,1H),4.12(dd,J＝10.0,1.2Hz,1H),4.09(dd,J＝9.6,2.8Hz,1H),3.99(ddd,J＝10.1,4.8,2.8Hz,1H),1.18–1.12(m,21H),1.08(s,9H),and1.01(s,9H). 13 C NMR(CDCl 3 ,101MHz)δ:151.17,134.35,128.77,128.34,125.20,101.42,77.68,73.16,71.92,66.29,27.63,27.13,22.93,20.05,18.37,18.35,and12.68.IR(thin film,cm -1 ):2933,2862,1654,1470,1339,1279,1260,1161,1110,1086,1021,889,825,760,and 752cm -1 .HRMS(DART-TOF)calculated for C 29 H 50 NaO 4 Si 2 + [M+Na] + m/z 541.3140,found 541.3141.
(38) 1-phenyl-3, 4, 6-tribenzyloxy-D-galactan (16 c)
alpha-O-alkenylsulfone prepared in example 1, 15c (0.15mmol, 83.4 mg), phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give compound 16c (53.2mg, 0.11mmol, yield 72%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.62–7.57(m,2H),7.37–7.23(m,18H),5.41(dd,J＝3.2,0.8Hz,1H),4.88(d,J＝12.0Hz,1H),4.71–4.66(m,3H),4.52(d,J＝12.0Hz,1H),4.48(d,J＝12.0Hz,1H),4.37–4.41(m,1H),4.35–4.31(m,1H),4.06–4.03(m,1H),3.90(dd,J＝10.4,5.6Hz,1H),and3.82(dd,J＝10.4,5.6Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:151.96,138.73,138.60,138.30,134.83,128.67,128.51,128.50,128.41,128.17,127.92,127.77,127.74,127.67,127.62,125.34,96.29,76.24,73.53,73.30,71.82,71.28,71.23,and68.48.IR(thin film,cm -1 ):3061,3028,2922,2859,1451,1275,1260,1083,1026,764,749,and 694cm -1 .HRMS(DART-TOF)calculated for C 33 H 32 NaO 4 + [M+Na] + m/z 515.2193,found 515.2200.
(39) 1-phenyl-3, 4-dibenzyloxy-D-fucosylene (16D)
alpha-O-alkenylsulfone prepared in example 1, 15d (0.15mmol, 67.5mg), phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give 16d (40.6mg, 0.11mmol, yield 70%) as a colorless oily compound. 1 H NMR(CDCl 3 ,400MHz)δ:7.64–7.57(m,2H),7.43–7.24(m,13H),5.40(dd,J＝2.8,1.2Hz,1H),4.96(d,J＝12.0Hz,1H),4.76(d,J＝12.0Hz,1H),4.74(d,J＝12.0Hz,1H),4.71(d,J＝12.0Hz,1H),4.40(ddd,J＝4.3,3.0,1.2Hz,1H),4.25(qdd,J＝6.7,2.0,1.1Hz,1H),3.78(ddd,J＝4.4,2.0,1.2Hz,1H),and1.41(d,J＝6.4Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:152.43,138.86,138.79,135.14,128.55,128.37,128.35,128.16,127.70,127.65,125.30,95.75,73.55,73.30,73.09,71.16,and16.61.IR(thin film,cm -1 ):3028,2929,2853,1495,1450,1276,1261,1100,1063,1025,765,749,730,and 693cm -1 .HRMS(DART-TOF)calculated for C 26 H 26 NaO 3 + [M+Na] + m/z 409.1774,found 409.1781.
(40) 1-phenyl-3, 4-dibenzyloxy-L-rhamnosene (16 e)
alpha-O-alkenylsulfone 15e (0.15mmol, 67.5mg), phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) prepared in example 1 according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to obtain compound 16e as a white solid (49.8mg, 0.13mmol, yield 86%). 1 H NMR(CDCl 3 ,400MHz)δ:7.60–7.55(m,2H),7.41–7.27(m,13H),5.42(d,J＝2.8Hz,1H),4.91(d,J＝11.6Hz,1H),4.74(d,J＝11.6Hz,1H),4.73(d,J＝11.6Hz,1H),4.66(d,J＝11.6Hz,1H),4.40(dd,J＝6.5,2.8Hz,1H),4.13(dq,J＝9.0,6.4Hz,1H),3.59(dd,J＝9.1,6.5Hz,1H),and1.50(d,J＝6.4Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:153.08,138.71,138.46,134.73,128.76,128.56,128.54,128.26,128.12,127.90,127.88,127.76,125.31,96.41,79.74,77.70,74.54,74.07,70.68,and17.74.IR(thin film,cm -1 ):3028,3005,2989,2931,2862,1276,1260,1099,1063,764,750,and 694cm -1 .HRMS(DART-TOF)calculated for C 26 H 26 NaO 3 + [M+Na] + m/z 409.1774, found 409.1778, melting point 73.5-74.9 deg.C
(41) 1-phenyl-3, 4-dibenzyloxy-D-arabinoxene (16 f)
alpha-O-alkenylsulfone prepared in example 1 (0.15mmol, 65.4 mg), phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) according to standard procedures 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in t-butanol (1.0 mL) was stirred at 60 ℃ for 12 hours. And (3) performing column chromatography separation, wherein an eluent is petroleum ether/ethyl acetate =10, and the separation purity is as followsThis gave 16f (43.0 mg,0.12mmol, 77% yield) as a colorless oily substance. 1 H NMR(CDCl 3 ,400MHz)δ:7.57–7.53(m,2H),7.43–7.27(m,13H),5.43(d,J＝5.2Hz,1H),4.77(s,2H),4.72(d,J＝12.0Hz,1H),4.65(d,J＝12.4Hz,1H),4.27(dd,J＝10.4,10.4Hz,1H),4.21–4.16(m,2H),and3.84(ddd,J＝10.4,3.8,3.8Hz,1H). 13 C NMR(CDCl 3 ,101MHz)δ:154.38,139.04,138.24,134.82,128.93,128.58,128.50,128.27,128.01,127.93,127.89,127.68,125.40,95.02,73.38,71.27,71.14,67.82,and63.91.IR(thin film,cm -1 ):3027,3005,2988,2927,2854,1275,1260,1088,1026,764,749,and 693cm - 1 .HRMS(DART-TOF)calculated for C 25 H 24 NaO 3 + [M+Na] + m/z 395.1618,found 395.1624.
(42) 1-phenyl-3, 4-dibenzyloxy-D-xyloxene (16 g)
According to standard procedures, 15g (0.15mmol, 65.4 mg) of the α -O-alkenylsulfone prepared in example 1, phenylboronic acid (0.30mmol, 36.6 mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give 16g (46.3mg, 0.12mmol, 83% yield) of the compound as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.65–7.59(m,2H),7.38–7.26(m,13H),5.49(dd,J＝4.8,1.2Hz,1H),4.69(d,J＝12.4Hz,1H),4.67(d,J＝12.4Hz,1H),4.65(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),4.32(ddd,J＝12.0,4.8,1.2Hz,1H),4.15(dd,J＝11.6,2.0Hz,1H),4.06(ddd,J＝4.8,3.2,1.2Hz,1H),and3.78–3.74(m,1H). 13 C NMR(CDCl 3 ,101MHz)δ:154.38,138.63,138.19,135.05,128.85,128.61,128.58,128.23,127.95,127.91,127.87,127.81,125.40,95.14,72.85,71.34,71.00,70.34,and64.85.IR(thin film,cm -1 ):3028,3006,2988,2924,2863,1451,1276,1260,1095,1055,1026,764,749,and 693cm -1 .HRMS(DART-TOF)calculated for C 25 H 24 NaO 3 + [M+Na] + m/z 395.1618,found 395.1620.
(43) 1-phenyl-hexabenzyloxy-D-malto-ene (16 h)
The α -O-alkenyl sulfone prepared in example 1 was 15h (0.10mmol, 98.8mg), phenylboronic acid (0.20mmol, 24.4mg), ni (COD) 2 (0.02mmol,5.5mg),Cy 3 PHBF 4 A mixture of (0.04mmol, 14.7 mg), and KOH (0.40mmol, 22.4 mg) in tetrahydrofuran (1.0 mL) was stirred at 60 ℃ for 12 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =10, to give 16h (85.1mg, 0.09mmol, 92%) of the compound as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.63–7.57(m,2H),7.35–7.22(m,31H),7.12(m,2H),5.55(d,J＝3.6Hz,1H),5.44(d,J＝3.6Hz,1H),4.93(d,J＝10.8Hz,1H),4.80(d,J＝10.8Hz,1H),4.78(d,J＝10.8Hz,1H),4.66(d,J＝11.2Hz,1H),4.65(s,2H),4.57(s,1H),4.56(d,J＝12Hz,1H),4.53(d,J＝11.6Hz,1H),4.47(d,J＝10.8Hz,1H),4.48–4.40(m,2H),4.35(d,J＝12Hz,1H),4.32(dd,J＝7.2,5.2Hz,1H),3.95(dd,J＝11.2,5.2Hz,1H),3.92(dd,J＝9.6,8.8Hz,1H),3.91-3.86(m,1H),3.85(dd,J＝11.2,3.6Hz,1H),3.67(dd,J＝10.0,9.2Hz,1H),3.61(dd,J＝10.8,2.8Hz,1H,H 6b ),3.57(dd,J＝9.6,3.6Hz,1H),and3.49(dd,J＝10.8,2.0Hz,1H,H 6a ). 13 C NMR(CDCl 3 ,101MHz)δ:153.23,139.05,138.61,138.58,138.45,138.28,138.14,134.65,128.90,128.55,128.50,128.45,128.43,128.40,128.30,128.07,128.02,127.99,127.98,127.84,127.73,127.72,127.70,127.67,127.61,127.60,127.59,125.37,96.21,95.73,81.99,79.82,77.75,77.22,76.17,75.70,75.11,73.57,73.52,72.89,70.94,70.13,68.98,68.45,and68.41.IR(thin film,cm -1 ):3028,3006,2989,2862,1452,1275,1260,1068,1027,764,749,and 695cm -1 .HRMS(DART-TOF)calculated for C 60 H 60 NaO 9 + [M+Na] + m/z 947.4130,found 947.4128.
When the starting alpha-O-alkenylsulfone is a mixture of two isomers of E/Z, the reaction results in the same product when either the E or Z isomer alone is used.
(44) 1- (1-methoxy-2-styryl) -4-methylbenzene (21 a)
With reference to standard operating procedures, the α -O-alkenylsulfone 19a (0.30mmol, 82.3mg, 1.0equiv) prepared in example 1, p-tolylboronic acid (0.60mmol, 81.6mg, 2.0equiv), ni (COD) 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) were stirred in tetrahydrofuran (1.5 mL) at 60 ℃ for 8 hours. Column chromatography was performed with petroleum ether/ethyl acetate =25 as eluent to give compound 21a (56mg, 0.25mmol, 83% yield, mixture of two inseparable isomers E and Z) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.72–7.66(m,1.32H),7.47–7.41(m,1.32H),7.33(t,J＝7.6Hz,1.36H),7.26–7.16(m,2.40H),7.13–6.95(m,2.60H),6.05(s,0.64H,E-isomer),5.78(s,0.36H,Z-isomer),3.77(s,1.08H,Z-isomer),3.61(d,J＝1.0Hz,1.92H,E-isomer),2.37(s,1.92H,E-isomer),and2.31(s,1.08H,Z-isomer). 13 C NMR(CDCl 3 ,101MHz)δ:157.47,156.51,138.52,138.41,137.24,136.20,133.64,133.44,129.31,129.29,129.01,128.95,128.66,128.48,128.06,126.68,126.52,125.24,112.18,101.33,57.98,55.57,21.47,and21.38.IR(thin film,cm -1 ):3021,2933,2835,1631,1510,1446,1276,1199,1119,1063,819,764,750,and 694cm -1 .HRMS(DART-TOF)calculated for C 16 H 16 NaO + [M+Na] + m/z 247.1093,found 247.1098.
(45) 1- (1-methoxy-4-methylpentyl-1-enyl) -4-methylbenzene (21 b)
By reference to standard procedures, the α -O-alkenyl sulfone 19b (0.30mmol, 76.2mg,1.0 equi) prepared in example 1v), p-tolylboronic acid (0.60mmol, 81.6mg, 2.0equiv), ni (COD) 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) were stirred in tetrahydrofuran (1.5 mL) at 60 ℃ for 8 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =25, to give compound 21b (43mg, 0.21mmol, 70% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.37–7.32(m,1.5H),7.26–7.23(m,0.5H),7.17–7.12(m,2.0H),5.26(t,J＝7.2Hz,0.74H,E-isomer),4.71(t,J＝7.2Hz,0.26H,Z-isomer),3.62(s,0.78H,Z-isomer),3.50(s,2.22H,E-isomer),2.34(s,3H),2.15(t,J＝7.2Hz,1.48H,E-isomer),1.95(t,J＝7.1Hz,0.52H,Z-isomer),1.69(hept,J＝6.7Hz,0.74H,E-isomer),1.59(hept,J＝6.7Hz,0.26H,Z-isomer),0.95(d,J＝6.7Hz,4.44H,E-isomer),and0.87(d,J＝6.7Hz,1.56H,Z-isomer). 13 C NMR(CDCl 3 ,101MHz)δ:155.77,155.19,137.71,137.55,133.87,133.44,129.16,128.80,128.72,126.01,112.87,99.14,58.49,55.09,36.53,34.68,29.90,28.96,22.66,22.42,21.41,and21.29.IR(thin film,cm -1 ):2953,2868,1275,1260,1118,1078,822,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 14 H 20 NaO + [M+Na] + m/z 227.1406,found 227.1411.
(46) 1- (1-methoxy-5-triisopropylsiloxy-1-enyl) -4-methylbenzene (21 c)
With reference to standard procedures, α -O-alkenylsulfone 19c (0.30mmol, 124mg, 1.0equiv) prepared in example 1, p-tolylboronic acid (0.60mmol, 81.6mg, 2.0equiv), ni (COD) 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) were stirred in tetrahydrofuran (1.5 mL) at 60 ℃ for 8 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =25, to give compound 21c (98mg, 0.27mmol, 90% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.36–7.30(m,1.3H),7.28–7.24(m,0.7H),7.16–7.11(m,2H),5.28(t,J＝7.2Hz,0.62H,E-isomer),4.70(t,J＝7.2Hz,0.38H,Z-isomer),3.75(t,J＝6.5Hz,1.24H,E-isomer),3.66(t,J＝6.5Hz,0.76H,Z-isomer),3.61(s,1.14H,Z-isomer),3.51(s,1.86H,E-isomer),2.34(s,3H),2.32(q,J＝7.5Hz,1.24H,E-isomer),2.15(q,J＝7.5Hz,0.76H,Z-isomer),1.72–1.65(m,1.24H,E-isomer),1.65–1.60(m,0.76H,Z-isomer),1.07(m,13.02H,E-isomer),and1.03(m,7.98H,Z-isomer). 13 C NMR(CDCl 3 ,101MHz)δ:155.56,154.99,137.77,137.56,133.67,133.34,129.15,128.73,128.62,125.95,113.60,99.82,63.31,63.04,58.62,55.07,34.68,33.40,24.00,22.12,21.39,21.29,18.20,18.16,12.21,and12.17.IR(thin film,cm -1 ):2941,2864,1742,1462,1102,1071,882,821,680,and 657cm -1 .HRMS(DART-TOF)calculated for C 22 H 38 NaO 2 Si + [M+Na] + m/z 385.2533,found 385.2538.
(47) (R) -1- (1-methoxy-4, 8-dimethylnonyl-1, 7-dienyl) -4-methylbenzene (21 d)
With reference to standard procedures, α -O-alkenylsulfone 19d (0.30mmol, 97mg, 1.0equiv), p-tolylboronic acid (0.60mmol, 81.6mg, 2.0equiv), ni (COD) prepared in example 1 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) were stirred in tetrahydrofuran (1.5 mL) at 60 ℃ for 8 hours. Column chromatography was performed, eluting with petroleum ether/ethyl acetate =25, to give compound 21d (65mg, 0.24mmol, 78%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.36–7.31(m,1.5H),7.26–7.22(m,0.5H),7.17–7.11(m,2H),5.25(t,J＝7.2Hz,0.76H,E-isomer),5.15–5.09(m,0.76H,E-isomer),5.08–5.04(m,0.24H,Z-isomer),4.70(t,J＝7.2Hz,0.24H,Z-isomer),3.62(s,0.72H,Z-isomer),3.50(s,2.28H,E-isomer),2.35(s,3H),2.32–2.21(m,1H),2.18–2.08(m,1H),2.05–1.89(m,2H),1.68(s,3H),1.61(s,3H),1.55–1.45(m,1H),1.44–1.31(m,1H),1.26–1.14(m,1H),0.94(d,J＝6.6Hz,2.28H,E-isomer),and0.86(d,J＝6.7Hz,0.72H,Z-isomer). 13 C NMR(CDCl 3 ,101MHz)δ:155.81,155.28,137.71,137.55,133.85,133.44,131.20,131.17,129.15,128.79,128.72,126.01,125.10,125.08,112.65,98.86,58.47,55.10,37.04,36.75,34.58,34.26,33.33,32.76,25.87,25.85,25.75,21.41,21.30,19.86,19.61,17.79,and17.75.IR(thin film,cm -1 ):2956,2919,1275,1260,1075,822,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 19 H 28 NaO + [M+Na] + m/z 295.2032,found 295.2033.
Example 4 preparation of ketones Using the open alkenyl ethers prepared according to the invention
The open alkenyl ether (compounds 21a to 21 d) prepared in example 3 was dissolved in dichloromethane, cooled to 0 ℃ and trifluoroacetic acid (TFA, 10.0 equiv) was added. Stirred for 2 hours. TLC detection reaction is completed, saturated sodium bicarbonate is quenched, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, reduced pressure distillation and column chromatography separation are carried out, and the product ketone is obtained.
(1) 1-p-tolyl-2-acetophenone (22 a)
Using the open alkenyl ether 21a prepared in example 3 (0.22mmol, 49mg) and trifluoroacetic acid (2.2mmol, 250mg), dissolved in dichloromethane (1.6 mL) was stirred at room temperature for 2 hours according to standard procedures. Column chromatography was performed using petroleum ether/ethyl acetate 15 as eluent, to give compound 22a (23mg, 0.13mmol, 50% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.95–7.86(m,2H),7.34–7.28(m,2H),7.28–7.20(m,5H),4.25(s,2H),and2.39(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:197.38,144.08,134.92,134.28,129.56,129.44,128.89,128.76,126.92,45.55,and21.76.IR(thin film,cm -1 ):3027,3005,2905,1682,1333,1275,1260,814,764,750,and 696cm -1 .HRMS(DART-TOF)calculated for C 15 H 14 NaO + [M+Na] + m/z 233.0937,found 233.0944.
(2) 4-methyl-1-p-tolylpentanone (22 b)
Using the open alkenyl ether 21b (0.18mmol, 37mg) prepared in example 3 and trifluoroacetic acid (1.8mmol, 205mg), dissolved in dichloromethane (1.6 mL) was stirred at room temperature for 2 hours, according to the standard procedures. Column chromatography was performed with petroleum ether/ethyl acetate 15 as eluent to give compound 22b (24mg, 0.126mmol, 70% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.91–7.82(m,2H),7.28–7.21(m,2H),2.98–2.89(m,2H),2.40(s,3H),1.71–1.64(m,1H),1.64–1.59(m,2H),and0.94(d,J＝6.0Hz,6H). 13 C NMR(CDCl 3 ,101MHz)δ:199.55,142.68,133.76,128.35,127.32,35.66,32.53,27.03,21.58,and20.73.IR(thin film,cm -1 ):3005,2988,2956,1682,1275,1260,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 13 H 18 NaO + [M+Na] + m/z 2813.1250,found 213.1251.
(3) 5-hydroxy-1-p-tolylpentanone (22 c)
Using alkenyl ether 21c (0.18mmol, 65mg) prepared in example 3 and trifluoroacetic acid (1.8mmol, 205mg), the mixture was dissolved in methylene chloride (1.6 mL) and stirred at room temperature for 2 hours, according to the standard procedures. Distilling under reduced pressure, adding tetrahydrofuran solution (5 mL, 1M) of tetrabutylammonium fluoride, stirring at room temperature for 2 hr, quenching with saturated ammonium chloride solution, extracting with ethyl acetate, and extracting with anhydrous Na 2 SO 4 Drying and distilling under reduced pressure. Column chromatography was performed, eluting with petroleum ether/ethyl acetate 15, to give compound 22c as a colorless oil (73% yield over two steps). 1 H NMR(CDCl 3 ,400MHz)δ:7.89–7.82(m,2H),7.27–7.22(m,2H),3.67(t,J＝6.4Hz,2H),2.99(t,J＝7.1Hz,2H),2.41(s,3H),1.93(br s,1H),1.87–1.79(m,2H),and1.69–1.61(m,2H). 13 C NMR(CDCl 3 ,101MHz)δ:200.21,143.91,134.58,129.37,128.29,62.47,38.10,32.40,21.73,and20.41.IR(thin film,cm -1 ):3408,2931,2868,1674,1606,1449,1407,1275,1260,1229,1180,1057,1010,978,804,764,and 749cm -1 .HRMS(DART-TOF)calculated for C 12 H 16 NaO 2 + [M+Na] + m/z 215.1043,found 215.1029.
(4) (R) -4, 8-dimethyl-1-p-tolylnonyl-7-en-1-one (22 d)
Using open alkenyl ether 21d (0.108mmol, 28mg) prepared in example 3 and trifluoroacetic acid (1.08mmol, 123mg), dissolved in dichloromethane (1.6 mL) was stirred at room temperature for 2 hours, according to standard procedures. Column chromatography was performed, eluting with petroleum ether/ethyl acetate 15, to give compound 22d (26mg, 0.102mmol, 95% yield) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ:7.89–7.82(m,2H),7.28–7.23(m,2H),3.01–2.94(m,1H),2.94–2.86(m,1H),2.41(s,3H),1.86–1.72(m,3H),1.54(s,6H),1.52–1.47(m,1H),1.42–1.30(m,3H),1.25–1.14(m,1H),and0.93(d,J＝6.2Hz,3H). 13 C NMR(CDCl 3 ,101MHz)δ:200.43,143.79,134.73,129.39,128.31,89.43,40.69,37.01,36.27,32.53,31.53,25.70,21.75,21.22,and19.47.IR(thin film,cm -1 ):3004,2952,2871,1774,1681,1370,1275,1260,1214,1159,1137,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 18 H 26 NaO 2 + [M+Na] + m/z 281.1876,found 281.1881.
Example 5 preparation of diabetes drugs Using aryl glycoside prepared according to the present invention
The method becomes a new method for preparing the diabetes mellitus type II medicaments of the eggliflozin and the 2-deoxyeggliflozin, and comprises the following steps:
step 1:
1- (3- (benzo [ b ] thiophene-2-methyl) -4-fluorophenyl) -3,4, 6-tri-tert-butyldimethylsilyloxy-D-glucal (25)
Referring to the standard procedures, α -O alkenylsulfone 15a (0.30mmol, 189mg, 1.0equiv) prepared in example 1, borate 24 (0.45mmol, 166mg, 1.5equiv), ni (COD) 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) in tetrahydrofuran (1.5 mL) were stirred at 60 ℃ for 12 hours. Column chromatography (petroleum ether/ethyl acetate 8) afforded product 25 as a white solid. (192mg, 0.264mmol, 88%). 1 H NMR(CDCl 3 ,400MHz)δ:7.76–7.71(m,1H),7.68–7.63(m,1H),7.56(dd,J＝7.3,2.3Hz,1H),7.50(ddd,J＝8.6,5.0,2.3Hz,1H),7.32–7.28(m,1H),7.27–7.22(m,1H),7.04(t,J＝9.2Hz,1H),7.02(s,1H),5.17(d,J＝4.4Hz,1H),4.25(s,2H),4.17–4.14(m,1H),4.15–4.11(m,1H),3.98(dd,J＝11.2,6.9Hz,1H),3.88–3.85(m,1H),3.84(dd,J＝11.6,3.6Hz,1H),0.91–0.87(m,27H),0.12(s,6H),0.11(s,3H),0.10(s,3H)0.02(s,3H),and0.01(s,3H). 13 C NMR(CDCl 3 ,101MHz)δ:161.06(d,J＝248.0Hz),149.93,143.47,140.17,139.94,132.01(d,J＝3.5Hz),128.15(d,J＝4.3Hz),126.29(d,J＝16.2Hz),125.84(d,J＝8.2Hz),124.26,123.82,123.14,122.27,121.99,115.30(d,J＝22.4Hz),98.18,80.74,70.49,69.25,61.75,30.27(d,J＝3.3Hz),26.12,26.07,26.06,18.50,18.28,18.27,-3.83,-3.88,-3.97,-4.52,-5.11,and-5.16. 19 F NMR(CD 3 OD,376MHz)δ:–118.19.IR(thin film,cm- 1 ):2953,2929,2857,1726,1471,1275,1259,1102,835,764,and 749cm- 1 .HRMS(DART-TOF)calculated for C 39 H 63 FNaO 5 SSi 3 + [M+Na] + m/z 769.3580, found 769.3582 melting point: 156.3-157.9 ℃.
Step 2:
compound 25 (72.9mg, 0.1mmol, 1.0equiv) was dissolved in THF (2 mL), cooled to 0 deg.C, and BH was slowly added 3 THF (1.0M, 0.3mL,0.3mmol,3.0 equiv), was stirred for 12 hours. Adding 30% of H 2 O 2 (3.0 mL) A further 3M aqueous NaOH solution (3.0M)l). Stirred at room temperature for 24 hours. Diluting with dichloromethane (25 mL), sequentially using 20% NaHSO 3 (25 mL), saturated NH 4 Cl (25 mL), water (25 mL), and saturated brine (25 mL). Anhydrous Na for organic layer 2 SO 4 Drying, filtering and distilling under reduced pressure. The crude product was dissolved in THF (2 mL), tetrabutylammonium fluoride (TBAF, 1.0M in THF,0.33mL, 3.3eq.) was added, and the mixture was stirred at room temperature for 2 hours. Concentration and column chromatography (DCM/MeOH 20). 1 H NMR(CD 3 OD,400MHz)δ:7.72(d,J＝7.9Hz,1H),7.64(d,J＝7.7Hz,1H),7.42(dd,J＝7.4,2.2Hz,1H),7.35(ddd,J＝7.7,5.1,2.2Hz,1H),7.27(t,J＝7.4Hz,1H),7.25–7.18(m,1H),7.09(d,J＝9.2Hz,1H),7.05(d,J＝4.7Hz,1H),4.31–4.19(m,2H),4.11(d,J＝9.4Hz,1H),3.91–3.82(m,1H),3.68(dd,J＝12.0,4.7Hz,1H),and3.49–3.32(m,4H). 13 C NMR(CD 3 OD,101MHz)δ:162.28(d,J＝245.0Hz),145.47,141.99,141.61,137.73(d,J＝3.5Hz),132.28(d,J＝4.4Hz),129.84(d,J＝8.2Hz),127.94(d,J＝16.0Hz),125.70,125.27,124.49,123.46,123.35,116.39(d,J＝22.4Hz),83.35,82.70,80.26,77.01,72.38,63.60,and31.19(d,J＝3.4Hz). 19 F NMR(CD 3 OD,376MHz)δ:–121.56.IR(thin film,cm -1 ):3361,2925,1501,1457,1275,1260,1086,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 21 H 21 FNaO 5 S + [M+Na] + m/z 427.0986, found 427.0984, melting point 146.2-147.9 deg.C.
And 3, step 3:
compound 25 (72.9mg, 0.1mmol, 1.0eq.) was dissolved in the mixed solvent AcOEt/MeOH (5, 36mL), 10% Pd/C (150 mg) was added, and stirring was carried out under a hydrogen atmosphere for 24 hours. Filtering with diatomite, and distilling under reduced pressure. The crude product was dissolved in THF (2 mL) and tetrabutylammonium fluoride (TBAF, 1.0M in THF,0.33mL,3.3 eq.) was added. Stirring was carried out at room temperature for 2 hours, distillation under reduced pressure, and column chromatography (DCM/MeOH 20. 1 H NMR(CD 3 OD,400MHz)δ:7.71(d,J＝7.8Hz,1H),7.64(d,J＝7.6Hz,1H),7.39(d,J＝7.2Hz,1H),7.37–7.30(m,1H),7.30–7.17(m,2H),7.12–7.04(m,1H),7.02(s,1H),4.48(d,J＝11.4Hz,1H),4.24(s,2H),3.90(d,J＝11.6Hz,1H),3.79–3.62(m,2H),3.38–3.21(m,2H),2.14(d,J＝12.9Hz,1H),and1.68–1.50(m,1H). 13 C NMR(CD 3 OD,101MHz)δ:161.95(d,J＝244.7Hz),145.51,141.93,141.56,139.96(d,J＝3.6Hz),130.48(d,J＝4.3Hz),128.23(d,J＝5.5Hz),128.11(d,J＝2.3Hz),125.72,125.29,124.49,123.47,123.28,116.58(d,J＝22.4Hz),82.66,78.49,74.53,73.74,63.74,43.25,and31.20(d,J＝3.3Hz). 19 F NMR(CD 3 OD,376MHz)δ:–121.95.IR(thin film,cm -1 ):3348,2921,2847,1501,1275,1260,1064,1026,824,764,and 749cm -1 .HRMS(DART-TOF)calculated for C 21 H 21 FNaO 4 S + [M+Na] + m/z 411.1037,found 411.1042.
Example 6 preparation of diabetes drugs Using aryl glycoside prepared according to the present invention
1- (3- (benzo [ b ] thiophene-2-methyl) -4-fluorophenyl) -3-O-triisopropylsiloxy-4, 6-O-di-tert-butylsilyl-D-glucal-ene
Referring to the standard procedures, α -O-alkenylsulfone prepared in example 1, 15b (0.30mmol, 175mg, 1.0equiv), borate 24 (0.45mmol, 166mg, 1.5equiv), ni (COD) 2 (0.03mmol,8.25mg,0.1equiv),Cy 3 PHBF 4 (0.06mmol, 22.0mg, 0.2equiv), and KOH (0.60mmol, 33.6mg,2.0 equiv) in tetrahydrofuran (1.5 mL) were stirred at 60 ℃ for 12 hours. Column chromatography (petroleum ether/ethyl acetate 8). (102mg, 0.15mmol, 50%). 1 H NMR(CDCl 3 ,400MHz)δ:7.76–7.70(m,1H),7.65–7.63(m,1H),7.35–7.43(m,2H)，7.31–7.22(m,2H)，7.02(t,J＝9.6Hz,1H),7.00(s,1H),5.12(d,J＝2.3Hz,1H),4.54(dd,J＝2.3,6.8Hz,1H),4.30–4.25(m,1H),4.23(s,2H),4.10–4.05(m,2H),3.99–3.92(m,1H),1.17–1.08(m,21H),1.07(s,9H),and1.00(s,9H).IR(thin film,cm -1 ):2943,2860,1726,1471,1276,1259,1152,828,762,and 750cm -1 .HRMS(DART-TOF)calculated for C 38 H 55 FNaO 4 SSi 2 + [M+Na] + m/z 682.3344,found 682.3340。
Compound 27 (68.3mg, 0.1mmol, 1.0equiv) was dissolved in THF (2 mL), cooled to 0 deg.C, and BH was slowly added 3 THF (1.0M, 0.3mL,0.3mmol,3.0 equiv), stirred for 12 h. Adding 30% of H 2 O 2 A further 3M aqueous NaOH solution (3.0 mL) was added (3.0 mL). Stirred at room temperature for 24 hours. Diluting with dichloromethane (25 mL), sequentially using 20% NaHSO 3 (25 mL), saturated NH 4 Cl (25 mL), water (25 mL), and saturated brine (25 mL). Anhydrous Na for organic layer 2 SO 4 Drying, filtering and distilling under reduced pressure. The crude product was dissolved in THF (2 mL), tetrabutylammonium fluoride (TBAF, 1.0M in THF,0.33mL, 3.3eq.) was added, and the mixture was stirred at room temperature for 2 hours. Concentration and column chromatography (DCM/MeOH 20). 1 H NMR(CD 3 OD,400MHz)δ:7.72(d,J＝7.9Hz,1H),7.64(d,J＝7.7Hz,1H),7.42(dd,J＝7.4,2.2Hz,1H),7.35(ddd,J＝7.7,5.1,2.2Hz,1H),7.27(t,J＝7.4Hz,1H),7.25–7.18(m,1H),7.09(d,J＝9.2Hz,1H),7.05(d,J＝4.7Hz,1H),4.31–4.19(m,2H),4.11(d,J＝9.4Hz,1H),3.91–3.82(m,1H),3.68(dd,J＝12.0,4.7Hz,1H),and3.49–3.32(m,4H). 13 C NMR(CD 3 OD,101MHz)δ:162.28(d,J＝245.0Hz),145.47,141.99,141.61,137.73(d,J＝3.5Hz),132.28(d,J＝4.4Hz),129.84(d,J＝8.2Hz),127.94(d,J＝16.0Hz),125.70,125.27,124.49,123.46,123.35,116.39(d,J＝22.4Hz),83.35,82.70,80.26,77.01,72.38,63.60,and31.19(d,J＝3.4Hz). 19 F NMR(CD 3 OD,376MHz)δ:–121.56.IR(thin film,cm -1 ):3361,2925,1501,1457,1275,1260,1086,764,and 750cm -1 .HRMS(DART-TOF)calculated for C 21 H 21 FNaO 5 S + [M+Na] + m/z 427.0986, found 427.0984, melting point 146.2-147.9 deg.C.
And step 3:
compound 27 (68.3mg, 0.1mmol, 1.0eq.) was dissolved in a mixed solvent of AcOEt/MeOH (5, 36mL), 10% Pd/C (150 mg) was added, and stirring was carried out under a hydrogen atmosphere for 24 hours. Filtering with diatomite, and distilling under reduced pressure. The crude product was dissolved in THF (2 mL) and tetrabutylammonium fluoride (TBAF, 1.0M in THF,0.33mL,3.3 eq.) was added. Stirring was carried out at room temperature for 2 hours, distillation was carried out under reduced pressure, and column chromatography (DCM/MeOH 20). 1 H NMR(CD 3 OD,400MHz)δ:7.71(d,J＝7.8Hz,1H),7.64(d,J＝7.6Hz,1H),7.39(d,J＝7.2Hz,1H),7.37–7.30(m,1H),7.30–7.17(m,2H),7.12–7.04(m,1H),7.02(s,1H),4.48(d,J＝11.4Hz,1H),4.24(s,2H),3.90(d,J＝11.6Hz,1H),3.79–3.62(m,2H),3.38–3.21(m,2H),2.14(d,J＝12.9Hz,1H),and1.68–1.50(m,1H). 13 C NMR(CD 3 OD,101MHz)δ:161.95(d,J＝244.7Hz),145.51,141.93,141.56,139.96(d,J＝3.6Hz),130.48(d,J＝4.3Hz),128.23(d,J＝5.5Hz),128.11(d,J＝2.3Hz),125.72,125.29,124.49,123.47,123.28,116.58(d,J＝22.4Hz),82.66,78.49,74.53,73.74,63.74,43.25,and31.20(d,J＝3.3Hz). 19 F NMR(CD 3 OD,376MHz)δ:–121.95.IR(thin film,cm -1 ):3348,2921,2847,1501,1275,1260,1064,1026,824,764,and 749cm -1 .HRMS(DART-TOF)calculated for C 21 H 21 FNaO 4 S + [M+Na] + m/z 411.1037,found 411.1042.
In conclusion, when the alpha-O-alkenyl sulfone is used as the electrophilic reagent to carry out the Suzuki-Miyaura coupling reaction, the reaction raw material alpha-O-alkenyl sulfone has simple preparation and stable structure, and can overcome the defects of instability, difficult preparation and the like when the organic halide and the sulfonic acid are used as the electrophilic reagent of the Suzuki-Miyaura coupling reaction. Meanwhile, the reaction conditions of the reaction are mild, the heterocyclic ring and various functional groups can be compatible, the yield is high, and the large-scale process production can be realized. Meanwhile, the invention utilizes alpha-O-alkenyl sulfone as an electrophilic reagent to carry out Suzuki-Miyaura coupling reaction, can generate aryl glycoside and open-chain alkenyl ether with high yield, can also prepare type II diabetes drugs of eggliflozin and 2-deoxyeggliflozin, and has wide application.
Claims (15)
1. A preparation method of a medicine of eggliflozin for treating diabetes or a derivative thereof is characterized in that: it comprises the following steps:
(1) Reacting alpha-O-alkenyl sulfone, an organic boron reagent, a ligand, alkali and a catalyst in a solvent to obtain a compound I;
(2) Reducing and substituting the compound I to obtain a coarse product of the epropanal; or the compound I is reduced to obtain a crude product of the epropanal derivative;
(3) Purifying the crude product of the eprogralin or the crude product of the eprogralin derivative to obtain the eprogralin or the eprogralin derivative;
in step (1), the ligand is selected from Ph 3 P or Cy 3 P·HBF 4 (ii) a The alkali is selected from KOH or NaOH; the catalyst is a Ni-containing catalyst; the solvent is tetrahydrofuran or tert-butyl alcohol;
the Ni-containing catalyst is Ni (OAc) 2 Cy 3 PHBF 4 、NiBr 2 Cy 3 PHBF 4 、Ni(PPh 3 ) 2 Cl 2 、Ni(dppp)Cl 2 、Ni(COD) 2 Cy 3 PHBF 4 、Ni(PCy 3 ) 2 Cl 2 ；
In the step (1), the reaction temperature is 60-80 ℃; the reaction time is 8-16h;
wherein the alpha-O-alkenyl sulfone is of one of the following structural formulas:
the organoboron reagent is
The structural formula of the compound I is
In the compound I, the reaction mixture is subjected to reaction,
n and R 1 With alpha-O-alkenylsulphones
The substituent groups on the same;
the structural formula of the eprogliflozin or the eproflozin derivative is as follows:
2. the method of claim 1, wherein: in the step (1), the molar ratio of the alpha-O-alkenyl sulfone to the organoboron reagent to the ligand to the base to the catalyst in the reaction is 1-5; the mol/L ratio of the alpha-O-alkenyl sulfone to the solvent is 0.1-10.
3. The production method according to claim 2, characterized in that: in the reaction, the molar ratio of the alpha-O-alkenyl sulfone to the organoboron reagent to the ligand to the base to the catalyst is 1.5-2; the mol/L ratio of the alpha-O-alkenyl sulfone to the solvent is 0.1-0.2.
4. The production method according to claim 3, characterized in that: in the reaction, the molar ratio of alpha-O-alkenyl sulfone, organoboron reagent, ligand, base and catalyst is 1; the mol/L ratio of the alpha-O-alkenyl sulfone to the solvent is 0.2.
5. The method of claim 1, wherein:
the alpha-O-alkenyl sulfone is of one of the following structural formulas:
6. the production method according to any one of claims 1 to 4, characterized in that: in the step (1), the ligand is Cy 3 P·HBF 4 (ii) a The alkali is KOH; the catalyst is Ni (COD) 2 (ii) a The solvent is tetrahydrofuran.
7. The production method according to any one of claims 1 to 4, characterized in that: in the step (1), the reaction time is 12-16h.
8. The method of claim 1, wherein: in the step (2), the compound I is reduced and substituted to obtain a coarse product of the israagliflozin, the reduced compound I is dissolved in a solvent, the temperature is cooled to 0 ℃, a reducing agent is slowly added, and the mixture is stirred for 10-15 hours; the substitution is a reduction of the product to which 30% H is added 2 O 2 Then adding 3M NaOH aqueous solution, and stirring at room temperature for 20-25 h; after the substitution, purifying the substituted product;
wherein the molar ratio of the compound I to the reducing agent is 1-5; the mol/L ratio of the compound I to the solvent is 0.1; compound I and 3% 2 O 2 The mol/L ratio of (A) is 0.1; the mol/L ratio of the compound I to the NaOH aqueous solution is 0.1.
9. The method of claim 8, wherein: in the step (2), the molar ratio of the compound I to the reducing agent is 1-3; the mol/L ratio of the compound I to the solvent is 0.1; compound I and 3% 2 O 2 The molar volume ratio mol/L of (2) is 0.1; the mol/L ratio of the compound I to the NaOH aqueous solution is 0.1.
10. The method for producing according to claim 8, characterized in that: in the step (2), the compound I is reduced and substituted to obtain a crude product of the israzin, the reduced compound I is dissolved in tetrahydrofuran, the temperature is cooled to 0 ℃, borane-tetrahydrofuran is slowly added, and the mixture is stirred for 12 hours; the substitution is a reduction of the product to which 30% H is added 2 O 2 Then adding 3M NaOH aqueous solution, and stirring at room temperature for 24h; the purification is to dilute the substituted product with dichloromethane, wash, dry the organic layer, filter, and distill under reduced pressure.
11. The method of manufacturing according to claim 10, wherein: in step (2), the purification is carried out by diluting the substituted product with dichloromethane, and then successively using 20% of NaHSO 3 Saturated NH 4 Washing with Cl, water and saturated brine, and washing the organic layer with anhydrous Na 2 SO 4 Drying, filtering, and distilling under reduced pressure.
12. The method of claim 1, wherein: in the step (2), reducing the compound I to obtain a coarse product of the ipragliflozin derivative, dissolving the reduced compound I in a solvent, and reacting in a hydrogen environment under the action of a catalyst for 20-30 hours under stirring; after the reduction, purifying the reduced product;
wherein the mass volume ratio w/v of the compound I to the solvent is 1-550; the mass ratio of the compound I to the catalyst is 1.2-0.6.
13. The method of manufacturing according to claim 12, wherein: in the step (2), the mass volume ratio w/v of the compound I to the solvent is 1; the mass ratio of the compound I to the catalyst is 1.4-0.5.
14. The method of manufacturing according to claim 12, wherein: in the step (2), the solvent consists of ethyl acetate and methanol in a volume ratio of 5; the catalyst is 10% Pd/C; the stirring reaction time is 24 hours; the purification is carried out by filtering with diatomite and reduced pressure distillation.
15. The production method according to claim 1, characterized in that: and (3) dissolving the crude product in tetrahydrofuran, adding tetrabutylammonium fluoride, stirring at room temperature for 2 hours, carrying out reduced pressure distillation, and carrying out column chromatography separation.
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| WO2015000412A1 (en) * | 2013-07-02 | 2015-01-08 | 四川海思科制药有限公司 | Benzocyclobutene derivative and preparation method and pharmaceutical application thereof |
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