WO2019228874A1 - Stereoselective synthesis of enantiomerically-enriched pantolactone - Google Patents

Stereoselective synthesis of enantiomerically-enriched pantolactone Download PDF

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WO2019228874A1
WO2019228874A1 PCT/EP2019/063160 EP2019063160W WO2019228874A1 WO 2019228874 A1 WO2019228874 A1 WO 2019228874A1 EP 2019063160 W EP2019063160 W EP 2019063160W WO 2019228874 A1 WO2019228874 A1 WO 2019228874A1
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anyone
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Werner Bonrath
Frederic Bourgeois
Jonathan Alan Medlock
Christof Sparr
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Dsm Ip Assets B.V.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form

Definitions

  • the present invention relates to a stereoselective synthesis of enantiomerically en- riched pantolactone.
  • Pantolactone has two optically active enantiomers.
  • (R)-pantolactone which is the compound of formula (I)
  • pantothenic acid compound of formula (III)
  • Pantothenic acid which also known as vitamin B5
  • Pan- tothenic acid is an essential nutrient.
  • pantothenic acid instead of pantothenic acid, calcium pantothenate is often used in dietary supple- ments because, as a salt, it is more stable than pantothenic acid.
  • Natural sources of vitamin B5 are for example mushrooms, broccoli, cabbage, leg umes, salmon, eggs, fish, brewer’s yeast, nuts, milk, and dairy products like cheese, wheat, peanuts, soybeans, molasses, and collard greens.
  • vitamin B5 is by chemical synthesis.
  • An important starting material is, as said above, (R)-pantolactone.
  • An usual way to produce vitamin B5 is the reaction of calcium b-alaninate with (R)-pantolactone in boiling ethanol or metha- nol.
  • pantolactone which is (S)-pantolactone
  • (S)-pantolactone can be used as such or it can be used as intermediate in various synthesis.
  • (S)-panto- lactone can also be transformed into (R)-pantolactone.
  • the present invention relates to a two-step stereoselective synthesis of enantiomeri- cally enriched pantolactone, which allows the production of (R)-pantolactone and/or (S)-pantolactone in good yields and good optical purity.
  • the present invention relates to a two-step and one-pot synthesis of (R)- pantolactone in good yields and good optical purity and avoids the need for a resolu- tion step.
  • R is a C1-C10 alkyl moiety, which is substituted or un-substituted alkyl.
  • the first step (step (i)) is carried out in the presence of at least one specific organo- catalyst.
  • the reaction steps are discussed in more detail below.
  • the first step (step (i)) is carried out in the presence of a least one organo-catalyst.
  • the organo-catalyst has a pyrrolidine ring, which is substituted.
  • the organo-catalyst is a compound of formula (VII)
  • Ri is H, CHs or OH
  • R 2 is H, CHs or OH
  • R 3 is H or CH 3 ,
  • R 4 is H or CH 3 ,
  • R 5 and R 6 are independently from each other H or a moiety of formula (VIII)
  • R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC 4 alkyl group)
  • R 11 is H, CH 3 or forms together with R 10 a tetrazole ring, which can be substi- tuted (by a CrC 4 alkyl group), and
  • R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
  • R12 is an aromatic ring system or a C2-C 4 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
  • R7 is H or CH3
  • Rg is H or CH 3 ,
  • R5 is never identical to R6.
  • the substituent Rs or R6 contains a moiety, that can form a hydrogen bond.
  • organo-catalyst is a compound of formula (VI G)
  • R1 is H, CHs or OH
  • R 2 is H, CHs or OH
  • R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC 4 alkyl group)
  • R 11 is H, CH 3 or forms together with R 10 a tetrazole ring, which can be substi- tuted (by a CrC 4 alkyl group), and
  • R 12 is H or CH 3 when R 10 and Rn form a tetrazole ring, or
  • R 12 is an aromatic ring system or a C 2 -C 4 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
  • R 5 is never identical to R 6 .
  • R 1 is OH or CH 3 , then R 2 is H and
  • R 1 is H.
  • An especially preferred org a no-catalyst is a compound of formula (VN”a)
  • R1 is H, CHs or OH
  • R 2 is H, CHs or OH
  • R 10 is O or NR 13 , wherein R 13 forms together with Rn a tetrazole ring, which can be substituted (by CH 3 )
  • R 11 is H, CH 3 or forms together with R 10 a tetrazole ring, which can be substituted (by CH 3 ),
  • R 12 is H or CH 3 when R- and Rn form a tetrazole ring, or
  • R 12 is an aromatic ring system or a C 2 -C 4 alkyl group, which can be substituted with the provisos that
  • R1 is H.
  • Another especially preferred organo-catalyst is a compound of formula (VN”b)
  • R 1 is H, CHs or OH
  • R 2 is H, CHs or OH
  • R 10 is O or NR 13 , wherein R 13 forms together with Rn a tetrazole ring, which can be substituted (by CH3)
  • R 11 is H, CH 3 or forms together with R 10 a tetrazole ring, which can be substituted (by CH 3 ),
  • R I2 is H or CH 3 when R- and Rn form a tetrazole ring, or
  • R I2 is an aromatic ring system or a C 2 -C 4 alkyl group, which can be substituted with the provisos that
  • R1 is OH or CH3
  • R 2 is H
  • R 1 is H.
  • organo-catalyst of formula (VII) are the following ones of formula (Vila) - (VI Ig) and (ent-Vlla) - (ent-Vllg): and
  • organo-catalyst as described above are known. They are available commercially or they can be produced according to known methods.
  • the reaction of step (i) is usually carried out in a solvent (or a mixture of solvents).
  • solvents are alcohols, hydrocarbons, halogenated hydrocarbons (for exam- pie chloroform and dichloromethane), ethers, esters and amides (for example DMF).
  • ethers for exam- pie chloroform and dichloromethane
  • esters for example DMF
  • amides for example DMF
  • secondary and tertiary alcohols such as isopropanol (pro- pan-2-ol) and tert- butyl alcohol (2-methylpropan-2-ol)).
  • step (i) should not comprise any water. This means that the water content is kept to a minimum and that no water is added to the reaction mixture of step (i) intentionally. Therefore, another preferred embodiment of the present invention is a process as described wherein step (i) the reaction mixture does not comprise any water
  • the reaction is usually carried at temperatures of 0°C - 80°C, preferably 10°C - 40°C, more preferably 20°C - 30°C.
  • the amount of the organo-catalyst is usually from 0.1 - 10 mol-% (in regard to the starting material). Preferably from 1 - 5 mol-%.
  • the starting material (the compounds of formula (IV) and (V) are usually added in equimolar amounts. A slight excess of one of the compounds is acceptable as well.
  • step (ii) is a transfer hydrogenation.
  • the reaction of step (ii) is carried out in the presence of a hydrogen donor (such as a formate or an alcohol).
  • the transfer hydrogenation is catalyzed by at least one transition metal catalyst.
  • the transition metal catalyst can be added as such to the reaction mixture.
  • the transition metal catalyst can be formed by the addition of ligand and by the addition of the transition metal in the form of a salt.
  • the organo-catalyst of step (i) serves as ligand to form the transition metal catalyst used in step (ii).
  • the transition metal is added to the reaction mixture in the form of a salt.
  • Preferred transition metals are Ru, Ir, Rh, Fe, Co and Mn, more preferred are Ru, Ir and Rh.
  • the transition metals can be added in form of a salt (such as di- chloro(p-cymene)ruthenium(ll) dimer).
  • step (ii) is usually carried out at elevated temperatures.
  • the reaction temperature of step (ii) is between 20°C and 100 °C, more preferably be- tween 30°C and 70 °C.
  • the amount of hydrogen donor is between 1 and 2 mol-eq (in regard of the compound of formula (VI) or the compound of formula (VI’)).
  • the amount of the transition metal salt used to form the catalyst is between 0.01 and 10 mol-%, preferably 0.1 - 10 mol, more preferably 1 - 5 mol-%, in regard of the compound of formula (VI) or the compound of formula (VI’).
  • the following examples serve to illustrate the invention. If not otherwise stated the temperature is given in °C.
  • organocatalysts used are either commercially available or can be prepared using known methods. One method to prepare a range of organocatalysts is described be- low.
  • transition metal catalyst or the transition metal salt and the ligand were added to a solution of ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) from example 2.
  • the mixture was degassed, sodium formate was added and the mixture was stirred at the desired temperature until the reduction was complete.
  • the reaction mixture extracted with MTBE and the combined organic phases were dried, filtered and con- centrated in vacuo.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates stereoselective synthesis of enantiomerically enriched pantolactone.

Description

STEREOSELECTIVE SYNTHESIS OF ENANTIOMERICALLY-ENRICHED PANTO- LACTONE
The present invention relates to a stereoselective synthesis of enantiomerically en- riched pantolactone.
Pantolactone has two optically active enantiomers. (R)-pantolactone which is the compound of formula (I)
Figure imgf000002_0001
and (S)-pantolactone, which is the compound of formula (G)
Figure imgf000002_0002
(R)-Pantolactone is a starting material for the synthesis of calcium (R)-pantothenate (compound of formula (II))
Figure imgf000002_0003
which is the commercial form of pantothenic acid (compound of formula (III))
Figure imgf000002_0004
Pantothenic acid, which also known as vitamin B5, is a water-soluble vitamin. Pan- tothenic acid is an essential nutrient. There are many health benefits of vitamin B5, some of which include a healthy heart, lower stress levels, and applications in skin and hair care.
Instead of pantothenic acid, calcium pantothenate is often used in dietary supple- ments because, as a salt, it is more stable than pantothenic acid.
Natural sources of vitamin B5 are for example mushrooms, broccoli, cabbage, leg umes, salmon, eggs, fish, brewer’s yeast, nuts, milk, and dairy products like cheese, wheat, peanuts, soybeans, molasses, and collard greens.
An alternative way to obtain vitamin B5 is by chemical synthesis. An important starting material is, as said above, (R)-pantolactone. An usual way to produce vitamin B5 is the reaction of calcium b-alaninate with (R)-pantolactone in boiling ethanol or metha- nol.
The other enantiomer of pantolactone, which is (S)-pantolactone, can be used as such or it can be used as intermediate in various synthesis. Alternatively, (S)-panto- lactone can also be transformed into (R)-pantolactone.
Due to the importance of vitamin B5 and therefore the relevance of (R)-pantolactone as a starting material to produce vitamin B5 and for the use of (S)-pantolactone, there is always a need for an improved process of production of enantiomerically enriched pantolactone.
Nowadays there are several processes known to produce (R)-pantolactone as well as for (S)-pantolactone. There are chemical as well as biochemical methods to pro- duce (R)-pantolactone as well as (S)-pantolactone. Also, combinations of chemical and biochemical methods are known.
A summary of the most important synthesis of (R)-pantolactone are to be found for example in Ullmans Industrial Chemistry (Vitamins 8 Pantothenic Acid 2012, p.299- 308). A common way is to synthesize racemic pantolactone and resolve the enantio- mers, however this results in a maximum yield of 50%.
The present invention relates to a two-step stereoselective synthesis of enantiomeri- cally enriched pantolactone, which allows the production of (R)-pantolactone and/or (S)-pantolactone in good yields and good optical purity.
Preferably, the present invention relates to a two-step and one-pot synthesis of (R)- pantolactone in good yields and good optical purity and avoids the need for a resolu- tion step.
The newly found process of production of (R)-pantolactone has the following reaction schemes
Figure imgf000004_0001
The newly found process of production of (S)-pantolactone has the following reaction schemes
Figure imgf000004_0002
wherein R is a C1-C10 alkyl moiety, which is substituted or un-substituted alkyl.
The first step (step (i)) is carried out in the presence of at least one specific organo- catalyst. The reaction steps are discussed in more detail below.
Step (i)
Figure imgf000005_0001
The first step (step (i)) is carried out in the presence of a least one organo-catalyst.
The organo-catalyst has a pyrrolidine ring, which is substituted.
Preferably the organo-catalyst is a compound of formula (VII)
Figure imgf000005_0002
wherein
Ri is H, CHs or OH,
R2 is H, CHs or OH,
R3 is H or CH3,
R4 is H or CH3,
R5 and R6 are independently from each other H or a moiety of formula (VIII)
Figure imgf000006_0002
wherein
R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC4 alkyl group)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substi- tuted (by a CrC4 alkyl group), and
R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
R7 is H or CH3,
Rs is H or CH3, and
Rg is H or CH3,
with the proviso that R5 is never identical to R6. The substituent Rs or R6 contains a moiety, that can form a hydrogen bond.
More preferably the organo-catalyst is a compound of formula (VI G)
Figure imgf000006_0001
wherein
R1 is H, CHs or OH,
R2 is H, CHs or OH,
Rs and R6 are independently from each H or a moiety of formula (VIII)
Figure imgf000007_0001
wherein
R10 is O or NRi3, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by a CrC4 alkyl group)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substi- tuted (by a CrC4 alkyl group), and
R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
with the provisos that
R5 is never identical to R6, and
when R1 is OH or CH3, then R2 is H and
when R2 is OH or CH3, then R1 is H.
An especially preferred org a no-catalyst is a compound of formula (VN”a)
Figure imgf000007_0002
wherein
R1 is H, CHs or OH,
R2 is H, CHs or OH,
R10 is O or NR13, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by CH3)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substituted (by CH3),
R12 is H or CH3 when R- and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted with the provisos that
when Ri is OH or CH3, then R2 is H and
when R2 is OH or CH3, then R1 is H.
Another especially preferred organo-catalyst is a compound of formula (VN”b)
Figure imgf000008_0001
wherein
R1 is H, CHs or OH,
R2 is H, CHs or OH,
R10 is O or NR13, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by CH3)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substituted (by CH3),
RI2 is H or CH3 when R- and Rn form a tetrazole ring, or
RI2 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted with the provisos that
when R1 is OH or CH3, then R2 is H and
when R2 is OH or CH3, then R1 is H.
Especially preferred organo-catalyst of formula (VII) are the following ones of formula (Vila) - (VI Ig) and (ent-Vlla) - (ent-Vllg):
Figure imgf000009_0001
and
Figure imgf000010_0001
The organo-catalyst as described above are known. They are available commercially or they can be produced according to known methods.
The reaction of step (i) is usually carried out in a solvent (or a mixture of solvents). Suitable solvents are alcohols, hydrocarbons, halogenated hydrocarbons (for exam- pie chloroform and dichloromethane), ethers, esters and amides (for example DMF). Especially preferred are secondary and tertiary alcohols (such as isopropanol (pro- pan-2-ol) and tert- butyl alcohol (2-methylpropan-2-ol)).
The reaction mixture of step (i) should not comprise any water. This means that the water content is kept to a minimum and that no water is added to the reaction mixture of step (i) intentionally. Therefore, another preferred embodiment of the present invention is a process as described wherein step (i) the reaction mixture does not comprise any water The reaction is usually carried at temperatures of 0°C - 80°C, preferably 10°C - 40°C, more preferably 20°C - 30°C.
The amount of the organo-catalyst is usually from 0.1 - 10 mol-% (in regard to the starting material). Preferably from 1 - 5 mol-%.
The starting material (the compounds of formula (IV) and (V) are usually added in equimolar amounts. A slight excess of one of the compounds is acceptable as well.
Step (ii)
Figure imgf000011_0001
The reaction of step (ii) is a transfer hydrogenation. The reaction of step (ii) is carried out in the presence of a hydrogen donor (such as a formate or an alcohol).
The transfer hydrogenation is catalyzed by at least one transition metal catalyst.
The transition metal catalyst can be added as such to the reaction mixture.
Alternatively, the transition metal catalyst can be formed by the addition of ligand and by the addition of the transition metal in the form of a salt.
Furthermore, it is also possible that the organo-catalyst of step (i) serves as ligand to form the transition metal catalyst used in step (ii). In this case the transition metal is added to the reaction mixture in the form of a salt. These alternative ways how to obtain the transition metal catalyst could also be com- bined (which means that a catalyst can be added as well as a ligand and a transition metal salt).
Preferred transition metals are Ru, Ir, Rh, Fe, Co and Mn, more preferred are Ru, Ir and Rh.
As stated above, the transition metals can be added in form of a salt (such as di- chloro(p-cymene)ruthenium(ll) dimer).
The reaction of step (ii) is usually carried out at elevated temperatures. Preferably, the reaction temperature of step (ii) is between 20°C and 100 °C, more preferably be- tween 30°C and 70 °C.
In the reaction of step (ii), the amount of hydrogen donor is between 1 and 2 mol-eq (in regard of the compound of formula (VI) or the compound of formula (VI’)).
In the reaction of step (ii), the amount of the transition metal salt used to form the catalyst is between 0.01 and 10 mol-%, preferably 0.1 - 10 mol, more preferably 1 - 5 mol-%, in regard of the compound of formula (VI) or the compound of formula (VI’). The following examples serve to illustrate the invention. If not otherwise stated the temperature is given in °C.
Examples
The organocatalysts used are either commercially available or can be prepared using known methods. One method to prepare a range of organocatalysts is described be- low.
General procedure for preparation of various organocatalysts
An oven-dried flask was charged with Cbz-D-proline or Cbz-L-proline (1.00 eq.) or a proline derivative and dry dichloromethane (0.20 mol/L). The solution was cooled to 0 °C and triethylamine (1 .00 eq.) and isobutyl chloroformate (1.00 eq.) were added. The mixture was stirred for 0.5 h, and the relevant amine (1 .00 eq.) was added. The mixture was warmed to room temperature and stirred until complete conversion (mon- itored by TLC). The mixture was washed with aq. sat. NH4CI, aq. sat. NaHC03 and brine. Each aqueous layer was re-extracted with dichloromethane. The combined or- ganic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude intermediate could be purified or used in the following step without further purification. The intermediate (1.00 eq.) was dissolved in MeOH (0.40 mol/L), the flask was flushed with argon three times and Pd/C (10.0 wt.%, 5.00 mol%) was added in one portion. The mixture was evacuated and flushed with hydrogen five times. The black suspension was stirred at room temperature under a hydrogen atmosphere until com- plete conversion (monitored by TLC). The reaction mixture was filtered over a plug of celite and rinsed with methanol.
Example 1 - (R)-N-(2-hvdroxyethyl)pyrrolidine-2-carboxamide (ent-Vllb)
According to the procedure above: Cbz-D-proline (2.49 g, 10.0 mmol, 1.00 eq.), tri ethylamine (1.41 mL, 10.0 mmol, 1 .00 eq.), isobutyl chloroformate (1.30 mL, 10.0 mmol, 1.00 eq.) and ethanolamine (1.21 mL, 10.0 mmol, 1.00 eq.) were reacted to form the intermediate (2.08 g).
The intermediate (2.03 g, 6.94 mmol, 1 .00 eq.) and Pd/C (10.0 wt.%, 368 mg, 347 pmol, 5.00 mol%) yielded organocatalyst (ent-Vllb) as a colorless liquid (1.10 g, quant.). Example 2: General procedure for step (i) testing various orqanocatalvsts producing
(R)-ethyl-2-hvdroxy-3,3-dimethyl-4-oxobutanoate (VI)
To a vial containing the organocatalyst (0.01 mmol, 10.0 mol%) 0.20 ml. of a stock solution of isobutanal (91 .0 mI_, 1.00 mmol) and ethyl glyoxalate (50.0 wt.% in toluene, 198 mI_, 1.00 mmol) in t-BuOH (2.00 ml.) was added. The mixture was stirred at room temperature for 4 - 72 h. Conversion was measured by NMR or GC and enantiose- lectivity was determined by chiral HPLC.
The results of the experiment are shown in the table below. Where a negative enan- tioselectivity is reported, this means that the major isomer produced is (S)-isomer. It is clearly understood that if opposite enantiomer of the organocatalyst is used, the identical yield and enantioselectivity for (R)-ethyl-2-hydroxy-3,3-dimethyl-4-oxobuta- noate (VI) will be obtained
Figure imgf000014_0001
Comparative examples (Comp-A and Comp-B) were performed with organocatalysts A and B under the same conditions. Ph Ph
H2N NH2
Figure imgf000015_0001
A B
Figure imgf000015_0002
Example 3
To a solution of (R)-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (ent-Vllb, 79.1 mg, 500 pmol, 5.00 mol%) in t-BuOH (10.0 ml_), isobutanal (910 mI_,10.0 mmol, 1.00 eq.) and ethyl glyoxalate (50.0% in toluene, 1.98 ml_,10.0 mmol, 1.00 eq.) were added. The mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue purified by column chromatography (cyclohexane/ethyl ace- tate, 4:1 ) yielding ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) (1.47 g, 84%, 72% ee) as a colorless oil. 1 H NMR (400 MHz, CDCI3) d = 9.57 (1 H, s), 4.32 (1 H, s), 4.30- 4.18 (2H, m), 3.06 (1 H, br), 1.27 (3H, t), 1 .14 (3H,s), 1.05 (3H, s). The analytical data was in agreement with an authentic sample.
General procedure for transfer hydrogenation (step (ii))
The transition metal catalyst or the transition metal salt and the ligand were added to a solution of ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) from example 2. The mixture was degassed, sodium formate was added and the mixture was stirred at the desired temperature until the reduction was complete. The reaction mixture extracted with MTBE and the combined organic phases were dried, filtered and con- centrated in vacuo. Example 4
Ethyl (R)-2-hydroxy-3,3-dimethyl-4-oxobutanoate (VI) (74% ee) was reacted with 5 equivalents of sodium formate and 0.5 mol% of RuCI(p-cymene)[(S,S)-Ts-DPEN] in water at 40 °C. Full conversion was obtained after 17 hours yielding (R)-pantolactone (I) (72% ee)
Example 5 - One pot, sequential synthesis of (R) oantolactone (I)
To a solution of (R)-N-(2-hydroxyethyl)pyrrolidine-2-carboxamide (ent-Vllb, 237 mg, 1.50 mmol, 5.00 mol%) in t-BuOH (30.0 ml_), isobutanal (2.74 ml_, 30 mmol, 1.00 eq.) and ethyl glyoxalate (50.0 wt.% in toluene, 5.95 ml_, 30.0 mmol, 1.00 eq.) were added. The mixture was stirred at room temperature for 24 h. Water (150 ml.) was added and the solution was degassed with argon for 1 h, before (RuCl2(cymene))2 (91.9 mg, 150 mmol, 0.50 mol%) and sodium formate (10.2 g, 150 mmol, 5.00 eq.) were added. The mixture was stirred overnight. A solution of aq. HCI (1 M, 200 ml.) was added and the reaction mixture extracted with MTBE (3x 600 ml_). The combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane/ ethyl acetate, 2:1 ) yielding the product ((R)- pantolactone, 2.41 g, 62%, 70% ee) as a white solid. The analytical data was in agree- ment with an authentic sample.

Claims

Claims
1. Process for the production of a compound of formula (I)
Figure imgf000017_0001
wherein a first step (step (i))
a compound of formula (IV)
ormula (V)
Figure imgf000017_0002
wherein R is a C1-C10 alkyl moiety, which can be substituted or an un-substituted alkyl, are reacted to form a compound of formula (VI)
Figure imgf000017_0003
wherein R has the same meaning as defined above,
in the presence of at least one organo-catalyst,
and subsequently in a second step (step (ii))
the compound of formula (I) is formed by a transfer hydrogenation in the presence of hydrogen donor and a transition metal catalyst.
2. Process for the production of a compound of formula (G)
Figure imgf000018_0001
wherein a first step (step (i))
a compound of formula (IV)
ormula (V)
Figure imgf000018_0002
wherein R is a C1-C10 alkyl moiety, which can be substituted or an un-substituted alkyl are reacted to form a compound of formula (VI’)
Figure imgf000018_0003
wherein R has the same meaning as defined above,
in the presence of at least one organo-catalyst,
and subsequently in a second step (step (ii))
the compound of formula (G) is formed by a transfer hydrogenation in the presence of hydrogen donor and a transition metal catalyst.
3. Process according to claim 1 or claim 2, wherein the organo-catalyst has a pyrrolidine ring, which is substituted.
4. Process according to anyone of the preceding claims, wherein the organo-cat- alyst is a compound of formula (VII)
Figure imgf000019_0001
wherein
Ri is H, CHs or OH,
R2 is H, CHs or OH,
R3 is H or CH3,
R4 is H or CH3,
R5 and R6 are independently from each other H or a moiety of formula (VIII)
Figure imgf000019_0002
wherein
R10 is O or NRI3, wherein RI 3 forms together with Rn a tetrazole ring, which can be substituted (by a Ci-C4 alkyl group)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substi- tuted (a Ci-C4 alkyl group), and
R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
R7 is H or CH3,
Rs is H or CH3, and
Rg is H or CH3,
with the proviso that R5 is never identical to R6.
5. Process according to anyone of the preceding claims, wherein the organo-cat- alyst is a compound of formula (VII’)
Figure imgf000020_0001
wherein
Ri is H, CHs or OH,
R2 is H, CHs or OH,
R5 and R6 are independently from each H or a moiety of formula (VIII)
Figure imgf000020_0002
wherein
R10 is O or NRI3, wherein RI3 forms together with Rn a tetrazole ring, which can be substituted (by a Ci-C4 alkyl group)
R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substi- tuted (by a Ci-C4 alkyl group), and
R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a 02-04 alkyl group, which can be substituted, and the * marks the bond to the pyrrolidine ring,
with the provisos that
R5 is never identical to R6, and
when R1 is OH or CH3, then R2 is H and
when R2 is OH or CH3, then R1 is H.
6. Process according to anyone of the preceding claims, wherein the organo-cat- alyst is a compound of formula (VN”a)
Figure imgf000021_0001
wherein
Ri is H, CHs or OH,
R2 is H, CHs or OH,
Rio is O or NRis, wherein RI3 forms together with Rn a tetrazole ring, which can be substituted (by CH3)
R11 is H, CH3 or forms together with Rio a tetrazole ring, which can be substituted (by
CH3),
RI2 is H or CH3 when R- and Rn form a tetrazole ring, or
RI2 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted with the provisos that
when Ri is OH or CH3, then R2 is H and
when R2 is OH or CH3, then Ri is H.
7. Process according to anyone of the preceding claims, wherein the organo-cat- alyst is a compound of formula (VN”b)
Figure imgf000021_0002
wherein
Ri is H, CHs or OH,
R2 is H, CHs or OH,
Rio is O or NRis, wherein R13 forms together with Rn a tetrazole ring, which can be substituted (by CHs) R11 is H, CH3 or forms together with R10 a tetrazole ring, which can be substituted (by
CH3),
R12 is H or CH3 when R10 and Rn form a tetrazole ring, or
R12 is an aromatic ring system or a C2-C4 alkyl group, which can be substituted with the provisos that
when R1 is OH or CH3, then R2 is H and
when R2 is OH or CH3, then R1 is H.
8. Process according to anyone of the preceding claims, wherein the organo-cat- alyst is chosen from the group consisting of
Figure imgf000022_0001
and
Figure imgf000023_0001
9. Process according to anyone of the preceding claims, wherein the reaction of step (i) is carried out in at least one solvent, preferably alcohols, hydrocarbons, halo- genated hydrocarbons (for example chloroform and dichloromethane), ethers, esters and amides (for example DMF).
10. Process according to anyone of the preceding claims, wherein the reaction mixture of step (i) does not comprise any water.
11. Process according to anyone of the preceding claims, wherein the reaction of step (i) is carried at temperatures of 0°C - 80°C, preferably 10°C - 40°C, more pref- erably 20°C - 30°C.
12. Process according to anyone of the preceding claims, wherein the amount of the organo-catalyst in step (i) is from 0.1 - 10 mol-%, preferably from 1 - 5 mol-%. (regarding the starting material).
13. Process according to anyone of the preceding claims, wherein the transfer hy- drogenation of step (ii) is catalyzed by at least one transition metal catalyst, which is added as such to the reaction mixture of step (ii).
14. Process according to anyone of the preceding claims 1 - 12, wherein the trans- fer hydrogenation of step (ii) is catalyzed by at least one transition metal catalyst, which is formed by the addition of ligand and by the addition of the transition metal in the form of a salt.
15. Process according to anyone of the preceding claims 1 - 12, wherein the trans- fer hydrogenation of step (ii) is catalyzed by at least one transition metal catalyst, wherein the organo-catalyst of step (i) serves as ligand to form the transition metal catalyst.
16. Process according to anyone of the preceding claims, wherein the transition metal is chosen from the group consisting of Ru, Ir, Rh, Fe, Co and Mn (preferably Ru, Ir and Rh).
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