WO1988000592A1

WO1988000592A1 - DIASTEROSELECTIVE STRECKER SYNTHESIS OF alpha-AMINOACIDS FROM GLYCOSYLAMINE DERIVATES

Info

Publication number: WO1988000592A1
Application number: PCT/EP1987/000371
Authority: WO
Inventors: Horst Kunz; Wilfried Sager; Waldemar Pfrenge; Mathias Decker
Original assignee: Shell Agrar Gmbh & Co. Kg
Priority date: 1986-07-18
Filing date: 1987-07-10
Publication date: 1988-01-28
Also published as: EP0274515A1; DE3624376A1

Abstract

O-acyl-protected glycosylamines, in particular 2,3,4,6-tetra-O-pivaloyl-$g(b)-D-galactopyranosylamine (1), their preparation and their use for the diastereoselective synthesis of $g(a)-aminoacids. With compounds such as (1), one can obtain by Strecker synthesis high yields and high diastereomer surplus. The direction of the asymmetric induction can be determined by the selection of the solvent. This type of synthesis is particularly effective when carried with Lewis acid catalysts. One obtains also high yields and high diastereoselectivity during Ugi four component synthesis facilitated by Lewis acids by using amines such as (1).

Description

Diastereoselective Strecker synthesis of α-amino acids from glycosulamine derivatives.

The invention relates to compounds of the formula

R - N = Q (I)

where Q represents two hydrogen atoms or the group

stands, where

R is a carbohydrate residue, preferably a residue of a hexose or pentose, the hydroxyl functions of which carry acyl protective groups and which is bonded to the nitrogen function via the anomeric carbon,

R ^{1 is} an aliphatic radical with 1-18 C atoms, which can also be substituted by oxygen or sulfur, or by CN, CONH or sulfonyl, an aromatic, optionally halogen, lower alkyl, lower alkoxy, cyano or nitro - Substituted radical, a heteroaromatic radical which contains at least one heteroatom from the group O, S and N as a ring member, or an optionally lower alkyl-substituted C ₃ -7 ₃ -cycloaliphatic radical

means, and the use of the compounds I for the diastereoselective synthesis of chiral amino compounds of the following formula III.

Phenyl and naphthyl are to be mentioned as aromatics, thiophene, furan and N-containing aromatics such as pyridine, pyrimidine, pyrazine, pyridazine as heteroaromatics. The aliphatic radicals can also be unsaturated if the length is appropriate. "Lower alkyl" or "lower alkoxy" may refer to branched groups with up to 4 carbon atoms. "Halogen" means fluorine, chlorine, bromine, iodine, especially chlorine.

The acyl protecting groups of the hydroxyl functions of the carbohydrates can contain aliphatic or aromatic hydrocarbon radicals. Branched aliphatic groups, such as e.g. in Pivaloyl. The compounds of the formula I can be used for the diasteroselective synthesis of chiral amino compounds of the formula

(III)

serve, wherein R and R ^{1 have} the above meaning and R ^{2 is} a denvat.ιsιerter carboxyl radical, preferably

-CN and -CONHR ⁴ , R ^{3 is} hydrogen or aliphatic C ₁ -C ₆ acyl, - 1 6 R ⁴ C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl or

-Cycloalkenyl or an optionally substituted aromatic radical.

To the extent that R ^{3 is} an aliphatic acyl, formyl and acetyl should be emphasized. If R ^{4 stands} for alkyl, the preferred meaning is tert-butyl. Particularly aromatic residues for R ₄ are phenyl and

Naphthyl into consideration, where the substituents specified for R ¹ may be present.

The (acylated) carbohydrate residue R in the formula I and

III and below is preferably derived from

Glucosyl, arabinosyl, mannosyl or galactosyl residue, the ß-D-galactopyranosyl residue should be emphasized. The synthesis of chiral compounds is gaining increasing interest, since increasing demands are being made on active substances with regard to the selectivity of their action. In this context, the amino acids and the peptides built up from them are of particular importance because they are, to a certain extent, natural active ingredients and can be used, inter alia, as pharmaceuticals, as flavorings and as dopants in animal feed. Several methods have been developed in recent years for the diastereoselective synthesis of α-amino acid derivatives. Most of these processes are carried out via metallized, especially lithiated, intermediate stages, whereby expensive metallizing agents, such as n-butyllithium, must be used and moisture and oxygen must be guaranteed. An example of these processes is the alkylation of the bis-lactim ethers of diketopiperazines according to Schöllkopf (U. Schöllkopf, Pure Appl.Chera.55 (1983), 1799).

An economical, industrially used amino acid synthesis is the Strecker synthesis (see e.g. the overview by A.Kleemann et al. In Ullmann's Encyclopedia of Industrial Chemistry, Vol. A2, 57,

5th edition, VCH Verl. Weinheim 1985).

Racernic mixtures are obtained, which have to be separated in separate steps.

Asymmetric Strecker syntheses were performed by K.Weinges and co-workers (Liebigs Ann.Chem. 1980, 212; ibid. 1985, 566) with 4S, 5S- (+) - 5-amino-2,2-dimethy1-4-phenyl- 1,3-dioxane performed. The optical induction is moderate according to this procedure. In some cases, however, pure diastereomers could be brought to crystallization. In Strecker syntheses with dipeptides as inducers, other authors observed high, but decreasing excesses of a diastereomer with increasing conversion. (S. Inoue et al. JCS Chem. Commun. 1981, 229). With the compounds I, which are the subject of this invention, a high asymmetric induction at high conversions is achieved in Strecker syntheses. Among the tested O-acetyl- and O-pivaloyl-protected glycosylamines I, 2, 3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosylamine 1 (synthesis: Example 1) proved to be the most effective. With a few exceptions, the profitable syntheses with the pivaloyl-protected Galactosy larain 1 are therefore reported below. The reactions proceed analogously with other glycosylamines, but generally with lower diastereoselectivity.

For the preparation of 1 is obtained from D-galactose Peπta-O-pivaloyl-ß-D-galactopyranose, which with trimethylsilyl azide / tin tetrachloride into the 2, 3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl azide is transferred. The amine 1 (Example 1) is obtained from this by reduction or by catalytic hydrogenation over platinum or Raney nickel:

The corresponding β-glucosyl-, α-mannosyl- (example 2) and the D- and L-arabinosylamines are obtained completely analogously. If the O-protected glycosylamines, such as 1, are reacted with aldehydes and sodium cyanide / acetic acid in the sense of a Strecker synthesis, the corresponding N-glycosyl-α-amino-nitriles are formed diastereoselectively in high yields. An interesting dependence of the direction of the optical induction on the solvent is observed, for example in the following reactions of galactosylamine 1:

Piv = (CH ₃ ) ₃ C-CO-

R '= CH ₃ , solvent: CHCl ₃ , (R): (S) = 1: 5, yield. 72%

R '= OCH ₃ , ": i-propanol, (R): (S) = 7: 2, yield 95%

The (S) -configured α-aminonitrile is preferably formed in chloroform, while the (R) -diastereomer is predominantly formed in isopropanol. Other C ₁ -C ₄ alcohols are also usable.

However, a considerable response time is required in both cases. The reaction in isopropanol requires 24 hours and in chloroform even 15 days.

A different procedure has therefore proven to be more favorable: First of all, the corresponding base is made from the glycosylamine and the aldehyde (see formula I, Q is II)

and then converts them with trimethylsilyl cyanide in the solvent 1 which effects the desired induction direction in the presence of Lewis acids, such as zinc (II) chloride, aluminum chloride or tin (IV) chloride. Depending on the amount of Lewis acid catalyst used, the reaction took place quantitatively in 10 min -24 h, again high diastereoselectivity being achieved. This process (Examples 3, 4, 5) is described by way of example using the example of m-chloro-benzylaldehyde.

With equimolar amounts of znCl ₂ , the reaction is complete after 10 minutes with the same induction. When the etch is worked up in isopropanol (Example 4), the (R) -

On sa i

Dias teredm ere pure. It can be isolated in a yield of approximately 65%.

It is noteworthy that even from the approach in which the (S) diastereomer is formed in excess, the (R) diastereomer slowly crystallizes out of methanol / water or n-heptane, so that in this way the (S ) -Diastereomers can be highly enriched.

Like the aromatic ones, the aliphatic aldehydes can also be used in these diastereoselective syntheses of α-amino nitriles, which is shown using the example of pivalaldehyde. Its reaction with 1 gives azomethine 4, which, with trimethylsilyl cyanide, provides α-aminonitrile 5 with high diastereoselectivity, a derivative of D-tert-leucine. This example shows that ZnCl ₂ can be replaced by SnCl ₄ with good success. (Example 6).

₃

This also crystallizes from the mixture 5 from aqueous methanol

Main diastereomers pure. It can be isolated in 80% yield. Instead of THF, other cyclic ethers, such as dioxane, can also be used.

The specified diastereomer ratios are obtained directly from the reaction mixture by HPLC (HPLC system from LKB with diode array detector) on RP columns (ODS II column, 3μ) in methanol / W as. water mixtures determined at a flow of 1 ml / min. To determine the configuration of the diastereomers, the product mixture formed from 1 with benzaldehyde in isopropanol was hydrolyzed with hydrochloric acid in water-dioxane, D-phenylglycine 7 being formed as an excess enantiomer; instead of dioxane, other water-miscible solvents, such as alcohols, can also be used, other strong acids can be used from acids, for example sulfuric acid.

From the retention times of the diastereomers analogous to 6, the configuration in the α-amino-nitrile part can be concluded for the other products.

(c-1.5, 16% aq. HCl) The reaction 6 → 7 also illustrates the conversion of the N-glycosylamino-nitriles into amino acids. In principle, the pivaloylated glycosyl compounds can be recovered. Type 1 glycosylamines also produce high asymmetric induction in other reactions involving amino compounds.

As an example, we carried out the four-component synthesis according to Ugi. For example, galactosylamine 1 reacts with p-nitrobenzaldehyde, zinc chloride, formic acid and tert-butyl isocyanide at 0 ° C in 1 h practically quantitatively to give the diastereomeric p-nitrophenylglycine derivatives 8, a diastereoselec ±

Yield approx. Quant .: (R) :( S) = 12.5: 1 after recrystallization from n-heptane / CH ₂ CL ₂ : pure (R) -diastereomeric yield. 81%

After only one recrystallization, the pure (R) -diastereomer 8 is obtained in 81% yield. (Example 7). In this reaction, thiophene-2-carbaldehyde can be used with equal success (Example 8). With pivalaldehyde, as an example of an aliphatic aldehyde, only a diastereomer of the tert-leucine derivative 9 (Example 9) is produced in virtually quantitative yield.

A second diastereomer is not detectable either in HPLC or in the high-field ¹ H and ¹³ C NMR spectra. The NMR spectra of the compounds of type 8/9 have signal doublings which are attributable to the rotamers of the formyl group.

If the pure diastereomer 8 is treated with catalytic amounts of Na methylate in methanol, the epimerization on the α-CH of the amino acid can be observed directly in part in the thin-layer chromatogram and in the NMR spectrum.

The four-component reaction (compare the formation of 8_) proceeds with the corresponding glucosylamine 10 in almost the same diastereoselectivity as the reaction with the thiophene-2-aldehyde shows. (Example 10).

(R): CS) = 11: 1

Overall, the glycosylamines are very effective optical inducers (auxiliaries), with which high diastereolectivity can be achieved with high, almost quantitative yields in reactions with amine participation, such as the Strecker synthesis and the Ugi reaction. In many cases, pure diastereomers can be obtained directly by crystallization. The glycosyl residue as an auxiliary group can be removed by acidic cleavage of the N-glycosidic bond. Interesting optically active compounds, such as α-amino acids, β-amino alcohols and 1,2-diamines, are available from the products.

Example 1:

A compound of the general formula I: 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosylamine 1

5.5 g (10 mmol) 2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl azide (Schrap. 92 ° C,

= -20.7 (c = 1, CHCI ₃ )) are hydrogenated in 200 ml of ethanol over 0.4 g of platinum dioxide. According to Abdest. of the solvent i.Vac. the remaining galactosylamine 1 is recrystallized from methanol. Educ. 4.95 g, 96%, = + 10-3

(c = 1, CHCl ₃ ), mp 88 ° C.

IR and ¹ H NMR spectra and elemental analysis correspond to structure 1.

Example 2:

2,3,4,6-tetra-O-pivaloyl-α-D-mannopyranosyl-amine

0.55 g (1 mmol) 2,3,4,6-tetra-O-pivaloyl-α -D-mannopyranosyl-azide (obtained from Penta-pivaloyi-mannopyranose; mp. 86-87 ° C,

= +84.5 (c = 1, CHCI3), are hydrogenated in 20 ml of ethanol over 40 mg of PtO ₂ , as described in the previous example, and the reaction solution is worked up analogously. Yield: 0.5 g, 98%; H

= + 4.1 (c = 2 'CHCI ₃ ); Elemental analysis and ¹ H-NMR spectrum correspond to the structure. Example 3:

Synthesis of a compound of general structure II: N- (m-chloro-benzylidene) -2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosylamine 2

10 g (20 mmol) of the pivaloyl-protected galactopyranosylamine 1 and 5.6 (40 mmol) m-chlorobenzaldehyde in 50 ml isopropanol are mixed with 30 drops of glacial acetic acid. After 30 min, the precipitated vessel is filtered off, see base 2 (quantitative) and recrystallized from isopropanol. Educ. 10.6 g (84%); Mp 135 ° C; l = -14.1 (c = 1, CHCl ₃ ).

¹³ C and ¹ H NMR spectra confirm the structure of 2. 1 ³ C NMR: δ = 159.3 (C = N), 92.8 (Cl).

Example 4:

Strecker synthesis with a glycosylarain - synthesis of a type III compound; Direction of the reaction to the (R) -diastereomer: N- (2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl) -m-chlorophenyl-glycino-nitri 13a

1 g (1.55 mmol) of the Schiff base 2 is stirred in 25 ml of isopropanol at 0 ° C. with 0.5 ml of trimethylsilyl cyanide (3.75 mmol) and 10 mg of ZnCl ₂ with exclusion of moisture for 24 h. Then you narrow i.Vak. to about 10 ml, add 50 ml of dichloromethane, shake the mixture twice with 50 ml of water, dry the organic phase over Na2so ₄ and evaporate the solvent in vacuo. from. According to HPLC analysis, the residue shows a diastereomeric ratio (R): (S) of 7: 1 (1.1 g ~ quantitative). After recrystallization from n-heptane, pure (R) -diastereomer is obtained according to HPLC: 0.69 g (66%). Mp 136 ° C, C = + 12.1 (c = 1, CHCl ₃ ), retention time:

t = 3'50 "(methanol / water 85:15, flow lml / min). The ¹³ C and ¹ H NMR spectra confirm the structure. 1 ³ C-NMR: α = 118.7 (C = N), 87.25 (C-1), 49.7 (α-C).

Example 5:

Strecker synthesis with the galactosylamine 1 analogous to Example 4, but directed towards the (S) -diaster eomer.

In an analogous approach, as given in Example 4, but in which 25 ml of chloroform is used as solvent at room temperature, a diastereomer mixture 3b of N-glycosylamino-nitriles is obtained quantitatively (1 g), in which, according to HPLC, the (S) - Diastereomers predominate: (R) :( S) = 1: 5. The Geraisch remains oily. The (R) -diastereomer, which is present in small amounts, crystallizes out very slowly from water / methanol.

The (S) -diastereomer is a retention time of t = 4'34 "under standard conditions (as Example 4) 1 ³ C-NMR:. Α = 118.6 (C = N), 86.4 (C-1), 49.3 (α - C).

Example 6:

Strecker synthesis with pivalaldehyde and the galactopyranosylamine 1: N- (2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl) -tert.leucine nitrile 5

1 g (2 mmol) of glycosylamine 1 and 1 ml of pivalaldehyde are stirred in 20 ml of n-heptane with 1 ml of an acidic ion exchanger IR 200. After 15 min, anhydrous MgSO ₄ is added and the mixture is filtered off after stirring for 5 min. The heptane is distilled off from the filtrate, and 10 ml of toluene in vacuo are removed twice from the remainder. evaporated. The remaining Schiff 'see Base II is dissolved in 15 ml of tetrahydro furan, cooled to -78 ° C, with 0.3 ml of trimethylsilyl cyanide and then mixed with 0.2 ml of SnCl ₄ . The mixture is stirred for 2 hours and then worked up as indicated in Example 4. The Geraisch shows a diastereomer ratio of (R) :( S) = 15: 1. After recrystallization from water / methanol, the main diastereomer is obtained in 82% yield. Mp 178 ° c = + 32.8 (c = 1, CHCI ₃ ); Ret.

Time: t = 4 '15 "in methanol-water 85:15. 1 ³ C-NMR: α = 119.6 (CN), 90.2 (Cl), 58.0 (αC-C).

Example 7:

Four-component reaction according to Ugi - Example of the synthesis of a compound of general formula III: N-formyl-N- (2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl) -p-nitro-phenyl -glycine-N-tert-butylamide 8

To 1 g (2 mmol) galactopyranosylamine 1, 0.32 g (2.1 mmol) p-nitrobenzaldehyde, 0.37 g (2 mmol) ZnCl ₂ and 0.1 g (2.1 mmol) formic acid (100%) in 20 ml absolute. Tetrahydrofuran is added at 0 ° C 0.174 g (2.1 mmol) of tert-butyl isocyanide and stirred for 1 h at 0 ° C, then for a further 12 h at room temperature. 50 ml of dichloromethane are added and the mixture is extracted with 200 ml of 2N Hydrochloric acid. It is washed with water, the organic phase is dried over MgSO ₄ and the solvent is evaporated down. distilled off. The product is obtained practically quantitatively: diastereomer ratio according to HPLC: 12.5: 1. After recrystallization from n-heptane / dichloromethane, the pure main (R) -diastereomer is obtained in 81% yield; Mp 138 ° C; = -35.6 (c = 1, CHCl ₃ ).

The elemental analysis as well as the ¹ H and ¹³ C NMR spectra correspond to structure 8. Signal doublings result from the rotamers of the formyl group. Example 8:

Four-component reaction according to Ugi with a heteroaromatic aldehyde: N-formyl-N- (2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyrano-syl) -2-thienyl-glycine-N- tert-butylamide

The reaction is carried out in the manner described in Example 7, but using thiophene-2-carbaldehyde instead of p-nitrobenzaldehyde. The diastereome ratio of the crude product is (R) :( S) = 25: 2. After chromatography on silica gel in petroleum ether / ethyl acetate (3: 1), pure (R) diaster eomer is obtained in 80% yield. Mp 124 ° C = -29.7 (c = 1, CHCl ₃ ).

Elemental analysis and ¹ H-NMR spectrum agree with the structure.

Example 9

Four-component reaction according to Ugi with an aliphatic aldehyde: N-formyl-N- (2,3,4,6-tetra-O-pivaloyl-ß-D-galactopyranosyl) - tert.-leucine-N-tert.- butylamide

In this reaction, appropriate amounts of pivalaldehyde are used instead of p-nitro-benzaldehyde. Otherwise, the reaction is carried out and worked up as indicated in Example 7. An oily product is obtained which solidifies amorphously and, according to HPLC, contains only one diastereomer of structure 9. An apparently α-configured by-product is present in a proportion of approx. 10%.

Educ. (from HPLC): 80%; [α] ²² = -4.9 (c = 1, CHCI ₃ ).

Retention time: 4 '33 "in methanol / water (87/13) with flow 1 ml / min again on column ODSII. Example 10:

Four component reaction with 2,3,4,6-tetra-O-pivaloyl-ß-D-glucopyranosylamine 10: N-formyl-N- (2,3,4,6-tetra-O-pivaloyl-ß -D-glucopyranosyl-2-thienyl-glycine-N-tert-butylamide 11

To a solution of 1 g (2.1 mmol) 2,3,4,6-tetra-O-pivaloyl-ß-D-glucopyranosylamine 10, 0.24 g (2.1 mmol) thiophene-2-carbaldehyde, 0.37 g ( 2 mmol) ZnCl ₂ and 0.1 g (2.1 mmol) formic acid (100%) in 20 ml absolute. THF is added at 0 ° C 0.174 g (2.1 mmol) of tert-butyl isocyanide, stirred for 1 h at 0 ° C and then for 24 h at room temperature. The work-up is carried out as indicated in Example 7 and gives in 88% yield oily mixture of diastereomers 11. Diastereomer ratio (R) :( S) = 11: 1 according to HPLC on ODSII column (3μ) in methanol / water (86/14) at a flow of 1 ml / min.) Retention time: (S ) = 3'43 ''; (R) = 4 '15''; -40.7 (c = 1, CHCl ₃ ).

Claims

1) Compounds of the formula

R - N = Q (I)

where Q represents two hydrogen atoms or the group

stands, where

R _{1 is} an aliphatic radical with 1-18 C atoms, which can also be substituted by oxygen or sulfur or by CN, CONH ₂ or sulfonyl, an aromatic, optionally halogen, lower alkyl, lower alkoxy, cyano or nitro - Substituted radical, a heteroaromatic radical which contains at least one heteroatom from the group O, S and N as a ring member, or an optionally lower alkyl-substituted C ₃ -C ₇ cycloaliphatic radical

means. 2) Compounds according to claim 1, characterized in that the acyl protective groups on the hydroxyl groups are pivaloyl radicals.

3) Compounds according to claim 1 and 2, characterized in that the carbohydrate residue belongs to the ß-D-glucopyranosyl or ß-D-galactopyranosyl series.

4) Process for the preparation of compounds according to Claim 1, 2 and 3, characterized in that the corresponding O-acyl-protected glycosyl azides are converted into the amines by reduction.

5) Process for the preparation of compounds according to claim 1, 2 and 3, characterized in that the carbohydrates are first converted into the penta-O-pivaloyl derivatives, which are then converted into the tetra-O-glycosyl azides, which then by reduction in the compounds of the invention according to claim 1, 2 and 3.

6) Process for the preparation of compounds of the formula I (with Q equal to the rest of the formula II), characterized in that a compound according to claim 1, 2 or 3, in which Q represents 2 hydrogen atoms, with aldehydes of the formula

O = CH - R ¹ (IV)

implements, wherein R ^{1 has} the above meaning. Has. 7) Method according to claim 6, characterized in that the reaction of the aldehyde with the compound of formula I is carried out under the conditions of a STRECKER synthesis or a four-component synthesis according to UGI.

8) Compounds of the formula

(III)

in which R and R _{1 have} the meaning given above and R ^{2 is} a derivatized carboxyl radical, preferably -CN and -CONHR ⁴ ,

R _{3 is} hydrogen or aliphatic

C ₁ -C ₈ acyl,

C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl or cycloalkenyl, or an optionally substituted aromatic radical

9) Compounds according to claim 7, in which R ^{2 is} a

Cyano group is.

10) Compounds according to claim 7, in which R ^{2 is} a

N-substituted carboxamide group and R ³

Is acyl residue.

11) Use of compounds according to claim 1, 2 and 3 in diastereoselective syntheses of compounds according to claim 7.