DE4200494A1 - New allyl silane derivs. - are intermediates for 3-oxa-carbacycline derivs., esp. with E configuration - Google Patents

Abstract

Allylsilane derivs. (I) are new. R1, R2 = a bond or R1 + R2 = R9-CH (R9 = 1-10C alkyl); R3, R4 = H, 1-10C alkyl, 5-7C cycloalkyl. 1-6C alkoxy, 6-10C aryl, 7-12C aralkyl, or when R1 + R2 form a bond, substd. propylene; R5 = H or alkyl, alkenyl or alkynyl with up to 20C opt. substd. by NH2, protected NH2, CH3NH, OH, COOH, SH or hal and opt. interrupted by O, S, NH or N(CH3); R6-R8 = 1-4C alkyl, 1-4C alkoxy or phenyl. Organozinc cpds. Zn(CH2SiR6R7R17)2 (IIIa) are also claimed. R17 = 1-4C alkoxy. Prepn. of (I) comprises reacting a cpd. of formula (II) with Zn(CH2SiR6R7R8)2 (III) where R15 = 1-4C alkyl or p-toluenesulphonyl. Free OH gps. in (II) are opt. protected and the reaction is carried out in the presence of NiCl2. (C6H5)2P(CH2)3P(C6H5)2 (=NiCl2dppp) as catalyst and with the addn. of a Li, Mg, or Zn salt. USE/ADVANTAGE - Cpds. (I) are intermediates for biologically active 3-oxa-carbacycline derivs. They are obtd. with high stereoselectivity in an E/Z ratio of 90:10 to 100:0 and are more suitable as intermediates than cpds. obtd. by EP 303562.

Description

The invention relates to allylsilane derivatives, a process for their preparation and their use as intermediates in the synthesis of biological active 3-oxa-carbacyclin derivatives.

German Offenlegungsschrift DE-OS 30 48 906 describes 3-oxa-prostacyclin Derivatives known. However, the process of making them is very complex.

From the European patent application EP 3 03 562 a method for Preparation of 2- (Bicyclo [3.3.0] -octan-3-ylidene) acetic acid derivatives of formula

with predominant E or Z content known, if necessary after reduction can be converted into the 3-oxa-carbacyclins, where Ra is a chiral Represents ester residue.

The disadvantage of this method is that, in whatever ratio always, both double bond isomers arise, but for the biological effective connections only the E-configured products are required.

So the task was to develop a method in which as exclusively as possible the E-configured isomer is formed.  

Phenylsulfoximines can be produced according to DE-OS 36 16 850 E-selectively.

It has now been found that the phenylsulfoximines of the formula II

with silicon-substituted organic zinc compounds with surprisingly particularly high stereoselectivity to the allylsilanes of the formula I. implemented, which are so far unknown and, as already mentioned, valuable Represent intermediate products.

The invention thus relates to allylsilane derivatives of the formula I.

wherein
R¹ and R² together form a bond or the rest

where R⁹ represents hydrogen or a C₁-C₁₀ alkyl radical,
R³ and R⁴ are identical or different and are hydrogen, C₁-C₁₀-alkyl, C₅-C₇-cycloalkyl, C₁-C₆-alkoxy, C₆-C₁₀-aryl, C₇-C₁₂-aralkyl or, if R¹ and R² together represent a bond, R³ and R⁴ together represent the substituted propylene

represent where
X is a bond, methylene or dimethylmethylene,
R¹⁰ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, -OSiR⁶R⁷R⁸, an ether or alkanoyloxy radical,
R¹¹ -CH₂R¹² with R¹² in the meaning of hydrogen, C₁-C₁₀-alkyl, hydroxy, C₁-C₁₀-alkoxy, -OSiR⁶R⁷R⁸, an ether or alkanoyl radical or the rest

-A-W-D-E-R¹³,

in which
A is a trans-CH = CH group or a -C≡C group,
W is a free or functionally modified hydroxymethylene or -C (CH₃) (OH) group, either
D is a C₁-C₅ alkylene group,
E -C≡C- or -CH = CH¹⁴ with R¹⁴ in the meaning of a hydrogen atom or a C₁-C₄ alkyl radical,
R¹³ C₁-C₄ alkyl or
DER¹³ together C₅-C₆-cycloalkyl or

R⁵ is hydrogen or an amino group which may be free or protected,
Methylamino, hydroxy, carboxy, mercapto or halogen substituted C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkynyl group, which may be replaced by -O-, -S-, -NH- or -N (CH₃) - can be interrupted, represents and
R⁶, R⁷, R⁸ are the same or different and are C₁-C₄-alkyl, C₁-C₄-alkoxy or phenyl.

The invention also relates to a method for producing allylsilane Derivatives of formula I.

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings given above have, which is characterized in that a phenylsulfoximine derivative of Formula II

wherein R¹, R², R³, R⁴ and R⁵ have the meanings given above, and R¹⁵ represents C₁-C₄ alkyl or p-toluenesulfonyl, optionally after protection free OH groups with an organic zinc compound of the formula III

Zn (CH₂SiR⁶R⁷R⁸) ₂ (III)

wherein R⁶, R⁷ and R⁸ have the meanings given above, under catalysis With

NiCl₂ · (C₆H₅) ₂P (CH₂) ₃P (C₆H₅) ₂

and with the addition of a lithium, magnesium or zinc salt is implemented.

The invention further relates to zinc compounds used in this process of the formula IV, in which R¹⁷ is C₁-C₄ alkoxy:

Zn (CH₂SiR⁶R⁷R¹⁷) ₂ (IV)

DE-OS 36 16 850 describes a production process for phenylsulfoximine Derivatives known.

Describe in the Journal of the American Chemical Society 1989, 111, 1125 I. Erdelmeier and H.-J. Gais the implementation of phenylsulfoximine derivatives with zinc alkyl or zinc aryl compounds.  

For the alkyl radicals R³, R⁴, R⁹, R¹⁰ and R¹² all come straight-chain and branched radicals with 1-10 C atoms into consideration, such as. B. methyl, ethyl, Propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, Neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl. Preferred Residues are those with 1-6 carbon atoms. Residues with 1-4 are particularly preferred C atoms.

Straight-chain or branched radicals come as unsubstituted alkyl radicals R⁵ with 1-20 C atoms in question, the radicals mentioned for R³, R⁴ and R⁹ for R⁵ are preferred.

The alkyl radicals R⁶, R⁷, R⁸, R¹³, R¹⁴ and R¹⁵ are said to have 1-4 carbon atoms be like B. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl.

The cycloalkyl radical R³ and R⁴ are cyclopentyl, cyclohexyl and cycloheptyl, as cycloalkyl radical DER¹³ meant cyclopentyl and cyclohexyl.

For the alkoxy groups R³ and R⁴ there are straight-chain or branched radicals 1-6 carbon atoms such as B. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy in question. Alkoxy groups are preferred with 1-4 carbon atoms.

The alkoxy groups R⁶, R⁷, R⁸ and R¹⁷ should be residues with 1-4 C atoms such as they have already been named for R³ and R⁴.

As alkoxy groups R¹⁰ and R¹² come straight-chain or branched radicals 1-10 C atoms, preferably 1-4 C atoms in question, as listed for R³ and R⁴ were.

With the aryl groups R³ and R⁴ are phenyl, 1-naphthyl and 2-naphthyl meant.

The aralkyl radicals R³ and R⁴ with 7-12 C atoms can, for. B. benzyl, phenethyl, Be 2-phenethyl, 3-phenylpropyl, 1-naphthylmethyl.  

The radicals R⁶, R⁷ and R⁸ of the silyloxy groups R¹⁰ and R¹² have the same Meanings such as the radicals R⁶, R⁷ and R⁸ of the allylsilane group in formula I. However, silyloxy groups can occur simultaneously in one molecule and also the allylsilane group independently substituted differently be.

As ether radicals R¹⁰ and R¹² come the radicals known to those skilled in the art Consider such as tetrahydropyranyl or tetrahydrofuranyl.

As alkanoyloxy R¹⁰ and R¹² come acetoxy, propionyloxy, butyryloxy and benzoyloxy in question.

The hydroxyl groups in W can be functionally modified, for example by etherification or esterification, the free or modified hydroxyl groups in W can be α- or β-permanent, whereby for the method above-mentioned protective groups are necessary, which later split off again can be.

Straight-chain or branched-chain, saturated ones come as alkylene group D. Alkylene radicals with up to 5 carbon atoms in question, which may be replaced by fluorine atoms, 1,2-methylene, 1,1-trimethylene, 1,1-tetramethylene, 1,1-pentamethylene can be substituted. Examples include: methylene, fluoromethylene, Ethylene, methylethylene, ethylethylene, trimethylene, tetramethylene, Pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene, 1,1-trimethyleneethylene, 1,1-tetramethylene methylene.

For the alkyl, alkenyl and alkynyl groups R⁵ come groups with 1-20 or 2-20 carbon atoms, which still have one or more groups Z₁ or Z₂ can contain how

- (CH₂) _mo - [Z₁- (CH₂) _mp ] _x - [Z₂- (CH₂) _mq ] _y -R¹⁶

in which
m = 2 to 20
o, p and q 16
x, y = 0, 1 or 2
Z₁ is a cis-CH = CH group, a trans-CH = CH group or a -C≡C group,
Z₂ -O-, S, an -NH-, an N-methyl group or a -C≡C group and
R¹⁶ mean free or protected amino, methylamino, hydroxy, carboxy, mercapto or halogen.

C₂-C₅ alkenyl or alkynyl groups R⁵ are preferred.

Under protected amino group R¹⁶ are to be understood: acyl such. B. acetyl, Propionyl or benzoyl, urethane protecting groups such. B. benzyloxycarbonyl, tert-butyloxycarbonyl or 9-fluorenylmethyloxycarbonyl and phthalidoyl. This is only intended to represent a selection of possible protective groups. Under Halogen as R¹⁶ means fluorine, chlorine and bromine.

Examples of the group R⁵ are

- (CH₂) ₅-NH₂, - (CH₂) ₆-NCH₃, - (CH₂) ₂-O, (CH₂) ₂- COOH, - (CH₂) ₂-O- (CH₂) ₃-NH₂, - (CH₂) ₂-O- (CH₂) ₂-O- (CH₂) ₂-OH, - (CH₂) ₃N (CH₂) ₃- NH₂, -CH₂C≡C- (CH₂) ₂-NH₂, - (CH₂) ₂-C≡C- (CH₂) ₂-NH₂, - (CH₂) ₂-C≡C- (CH₂) ₂-O- (CH₂) ₂-SH, -C≡C- (CH₂) ₄-NH₂, -C≡C- (CH₂) ₅-NH₂, -C≡C- (CH₂) ₃-C≡C- (CH₂) ₂-NH₂

Preferred are allylsilane derivatives, wherein
R¹ and R² together form a bond
R³ and R⁴ together represent the substituted propylene radical B,
R₅ is hydrogen or an alkynyl group substituted by OH, NH₂ or COOH,
R⁶, R⁷, R⁸ independently of one another C₁-C₄-alkyl, C₁-C₄-alkoxy or phenyl,
R¹¹ represents -AWDE-R¹³.

Such compounds are characterized, for example, by the formula Yes

The starting material for the process are those defined in the claim Alkylsulfoximine or the p-toluenesulfonic acid sulfoximine suitable. Prefers the methylsulfoximine (R¹⁵ = CH₃) is used.

Free hydroxy groups must be protected in the starting material for the process be.

The introduction of the protective groups as well as the later splitting off takes place according to the generally customary methods known to the person skilled in the art.

The lithium, magnesium or zinc salts required for the reaction can LiCl, LiBr, LiI, MgCl₂, MgBr₂, MgI₂, ZnCl₂ or ZnBr₂. To be favoured Magnesium salts, especially MgBr₂ used.

In a preferred process, compounds of the formula IIa

used in the R¹ and R² together a bond, R³ and R⁴ together the Propylene radical B, R⁵ is hydrogen and R¹⁵ is methyl.

For the process, z. B. diethyl ether, tetrahydrofuran, Ethylene glycol dimethyl ether and diethylene glycol dimethyl ether are suitable. Diethyl ether is preferably used.

The binding of the allylsilane compounds of formula I is at temperatures from -10 ° C to 36 ° C, preferably at room temperature.

The amount of zinc reagent used in the process can be based on the sulfoximine used are 1-3 equivalents.  

Because of the high reactivity of the zinc reagents, a reaction is necessary under protective gas such as B. argon or nitrogen and water exclusion absolutely required.

The allylsilane compounds of formula I obtained can easily by Oxidation with conventional oxidizing agents such. B. H₂O₂ in the corresponding Allyl alcohols are transferred. The stereochemistry of the double bond remains fully preserved even in this reaction.

The allylsilane compounds of the formula (Ia) according to the invention therefore represent valuable precursors for the synthesis of 3-oxa-carbacyclines. They are obtained with an E / Z selectivity of up to 99: 1. This ratio represents a significant improvement in terms of State of the art in which E / Z ratios of up to 91: 4 are obtained will.

The present invention must be considered particularly noteworthy since improvements in the E / Z ratios in the range between 90: 10 to 100: 0 are particularly difficult to reach.

The following examples serve to explain the invention further.

example 1 Bis - [(trimethylsilyl) methyl] zinc

0.1 mol (2.43 g) of Mg chips are placed in a 250 ml 2-necked flask submitted. After the attachment of a dropping funnel with a three-way valve and a reflux condenser, the apparatus is heated and vented with argon. 0.1 mol (chloromethyl) trimethylsilane (12.27 g, 14.0 ml) and 10 ml of anhydrous ether are in the Dropping funnels filled. While stirring, some of this solution dropped to the magnesium shavings and warmed up slightly. Around Some may facilitate the start of the Grignard reaction Drops of 1,2-dibromoethane are added. The reaction jumps usually without problems (clouding, warming). The approach is cooled with ice and by adding 20 ml each anhydrous ether in the reaction flask and the chlorosilane solution diluted. At 0 ° C the will within about 1 h Chlorosilane slowly added dropwise. Then there will be more Stirred at RT for 20 h. The content of the almost clear solution is titrated with benzyl alcohol against phenanthroline determined (90-95%).

According to the titrated content of the Grignard, 0.5 Equivalent anhydrous ZnCl₂ melted in an oil pump vacuum (to remove any remaining water) in ether dissolved and the solution obtained slowly at 0 ° C to the Grignard solution dripped. The solution soon clouded over and it came to mind white precipitate (MgCl₂). Full sales can due to phenanthroline (only very weak red coloring) and checked by quenching a sample with water (pH 7-8) will. After 3 d of stirring at room temperature, the batch filtered under argon to separate the MgCl₂ (G3 frit). With ice cooling, the almost clear filtrate is in an oil pump vacuum largely concentrated by stripping off the ether. The pure Zinc compound is obtained by distillation under argon in Oil pump vacuum (bp 65-70 ° C at 1 Torr) in one  Overall yield of 72% as a colorless, extremely pyrophoric Liquid. If air enters, there is immediate ignition!

1 H-NMR (250 MHz, CDCl₃):
δ = -0.51 (Zn-CH₂-), 0.01 (SiMe₃).

Example 2 [aR] - [1- [4- (1,1-dimethylethyl) cyclohexylidene] ether] trimethylsilane

61 mg (0.2 mmol) sulfoximine [R, aR] - [1- [4- (1,1-dimethyl) cyclohexylidene] methyl] -N-methyl-S-phenylsulfoximine (prepared according to DE-OS 36 16 850) and 10 mol% catalyst (11 mg NiCl₂ (C₆H₅) ₂P (CH₂) ₃P (C₆H₅) ₂ = NiCl₂dppp) are placed in a round bottom flask. After attaching a three-way valve, the flask is evacuated and aerated with argon. Then 10 ml of anhydrous ether are added. 3 equivalents of bis - [(trimethylsilyl) methyl] zinc are then added dropwise with a cannula under argon, followed by 3 equivalents of magnesium bromide etherate (as an ethereal, 2.8 molar solution). After 4 d stirring at room temperature, the conversion is complete (TLC sample). The orange-umbra colored approach is quenched by adding saturated (sat.) NaHCO₃ solution, extracted with hexane and filtered to separate the catalyst through a short silica gel column (elution with hexane to burn off the sulfinamide). After chromatography (flash chromatography (FL), eluent (LM) hexane, R _f (product) = 0.68), 43 mg (90%) of pure "cross-coupling" product are obtained as a colorless oil. The product crystallizes in the form of small needles in the freezer at -18 ° C. However, the melting point is below 0 ° C. The enantiomeric purity of the allylsilane obtained can be determined by means of ¹H shift NMR spectrum after adding 2 equivalents of Agfod / Pr (tfc) ₃ (silver-7,7-dimethyl-1,1,1,2,2,3,3-heptafluoro - 4,6-octanedionate / praseodymium [3- (trifluoromethyl-hydroxymethylene) - l-camphoate]) can be checked. Because of the instability of the silver complex, the NMR sample must be handled in the absence of light and measured immediately after preparation. In the presence of these shift reagents, the signals of the trimethylsilyl groups of the enantiomeric allylsilanes appearing at approximately -0.2 ppm are split up (DD = 0.04 ppm). When using d-Pr (tfc) ₃ (praseodymium [3- (trifluoromethyl-hydroxymethylene) -d-camphoate]) as a chiral shift reagent, the signal of the aR configured allylsilane appears, as determined by weighing and measuring a defined mixture of the enantiomers , in a higher field. In the presence of these shift reagents (Lewis acids), no detectable decomposition occurred with the allylsilanes within one day.

The ee value determined using this method is 95% (the other Enantiomer was undetectable).

[α] = -36.6, [α] = -16.8 (c = 0.262, hexane)

1 H-NMR (400 MHz, CDCl₃):
δ = -0.03 (SiMe₃), 9H), 0.83 (t-Bu, 9H), 0.85-1.02 (m, 3-Ha, 5- Ha, 2H), 1.13 (tt , J _4.3a = J _4.5a = 12.3 Hz, J _4.3e = J _4.5e = 3.8 H, 4-H, 1H), 1.38 (td, J _8.7 = 8 , 7 Hz, J _8.6a = J _8.2a = 1.5 Hz, 8-H, 2H), 1.60 (mt, J _{2a, 2e} = J _{2a, 3a} = 13.5 Hz, 2-Ha , 1H), 1.76-1.84 (m, 3-He, 5-He, 2H), 1.98 (mt, J _{6a, 6e} = J _{6a, 5a} = 13.5 Hz, 6-Ha, 1H), 2.19 (md, K _{6e, 6a} = 13.5 Hz, 6-He, 1H), 2.55 (md, J _{2e, 2a} = 13.5 Hz, 2-He, 2-He, 1H) 5.07 (tt, J _7.8 = 8.7 Hz, J _7.6a = J _7.2a = 1.8 Hz, 7-H, 1H). The assignments were made by decoupling and NOE experiments.

13 C-NMR (100 MHz, CDCl 3):
δ = -1.66 (Si ( C H₃) ₃), 17.90 (C-8), 27.73 (C ( C H₃) ₃), 28.32, 28.34 (C-3, C- 5), 29.55 (C-2 or C-6), 32.52 ( C (CH₃) ₃), 37.28 (C-2 or C-6), 48.69 (C-4), 116 , 41 (C-7), 136.99 (C-1).

IR (film):
2950, 1366, 1248, 1156, 1040, 855, 756, 695 cm ^-1 .

MS (EI, 70 eV):
m / z (%) = 238 (M⁺, 10), 164 (-SiMe₃, 10), 73 (SiMe₃⁺, 100), 57 (CMe₃⁺, 12).

C₁₅H₃₀Si (238.48)
Calculated:
C 75.54, H 12.68;
found:
C 75.36, H 12.58.

Example 3 [3aS- (2E, 3aα, 4α, 5β, 6aα)] - [[5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[[(1,1-dimethylethyl) dimethylsilyl] oxy] methyl] hexahydro-2 (1H) -pentalenylidene] -ethyl] - trimethylsilane

55 mg (0.1 mmol) of the sulfoximine [3aS- (2E (S *), 3aα, 4α, 5β, 6aα)] - [[5 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 - [[[((1,1-dimethylethyl -) - dimethylsilyl] oxy] methyl] hexahydro-2 (1H) - pentalenylidene] methyl] -N-methyl-S-phenylsulfoximine (produced according to DE-OS 36 16 850) and 10 mol% catalyst (5.5 mg NiCl₂dppp) are placed in a round bottom flask. After attaching a three-way valve, evacuating and venting with argon, 10 ml of anhydrous ether are added. 72 mg (0.3 mmol) of bis - [(trimethylsilyl) methyl] zinc and 3 equivalents of magnesium bromide etherate (as a 2.8 molar ethereal solution) are then added dropwise with a cannula. The catalyst dissolves within about 1 h and a yellow-brown clear solution is obtained. After 5 d at room temperature, only traces of starting material can be detected by means of thin layer chromatography. The solution is quenched with saturated NaHCO₃ solution, extracted with hexane, dried and filtered through a short silica gel column. After chromatography (flash chromatography (FL), mobile phase (LM) ethyl acetate (EE) / hexane 1:50, R _f (product) = 0.45), 42 mg (87%) of pure "cross-coupling" product are obtained as a colorless oil that does not become solid even at -18 ° C. The selectivity (E / Z isomer) is 99.5: 0.5 (HPLC). Signals from the Z isomer were no longer detectable in the 1 H-NMR spectrum (400 MHz). A small sample taken after 3 d has a selectivity of 99.3: 0.7. This fluctuation lies in the range of the measurement inaccuracy. So there is no epimerization during and after the reaction in the area of measurement inaccuracy.

[α] = +46.9, [α] = +12.2 (c = 0.343, hexane)

1 N-NMR (400 MHz, CDCl₃):
δ = -0.04 (s, SiMe₃, 9H), 0.00, 0.01, 0.02, 0.05 (s, SitBu Me₂ , 12H), 0.85, 0.88 (s, Si tBu Me₂, 18H), 1.19 (ddd, J _{6 β , 6 α} = 12.2 Hz, J _{6 β , 5 α} = 9.0 Hz, J _{6 β , 6a α} = 8.2 Hz, 6-Hβ , 1H), 1.36 (d, J _{1 ′, 2 ′} = 8.3 Hz, 1′-H, 2H), 1.44 (ddt, J _{4 β , 3a α} = J _{4 β , 5 α} = 9.0 Hz, J _{4 β , 7} = 5.1 Hz, J _{4 β , 7} = 3.8 Hz, 4-Hβ, 1H), 2.00 (md, J _{1 β , 1 α} = 15 Hz, 1-Hβ, 1H), 2.05-2.26 (m, 3-Hβ, 6-Hα, 3a-Hα, 1- Hα, 4H), 2.30 (dq, J _{6a α , 6 β} = J _{6a α , 3a α} = 8.2 Hz, J _{6a a , 1 α} = 3.8 Hz, 6a-Hα, 1H), 2.39 (m, 3-Hα, 1H), 3.57 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 5.1 Hz, 7-H, 1H), 3.62 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 3.8 Hz, 7-H, 1H), 3.83 (dt, J _{5 α , 6 β} = J _{5 α , 4 β} = 9.0 Hz, J _{5 α , 6 α} = 6.6 Hz, 5-Hα, 1H) , 5.22 (mt, J _{2 ′, 1 ′} = 8.3 Hz, 2′- H, 1H). The signals were assigned using NOE and decoupling experiments.

13 C-NMR (100 MHz, CDCl 3):
δ = -5.37, -5.27, -4.72, -4.36 (SitBu Me₂ ), -1.56 (SiMe₃), 18.15, 18.47 (Si tBu Me₂), 20.13 (C-1 ′), 25.97, 26.09 (Si tBu Me₂), 35.62, 39.69, 42.46 (C-1), C-3, C-6), 38.35, 41.46 (C-3a, C-6a), 55.65 (C-4), 62.32 (C-7), 74.08 (C-5), 116.75 (C-2 ′), 140.19 (C-2).

IR (film):
2955, 2930, 2875, 2860, 1472, 1463, 1390, 1361, 1250, 1110, 858, 837, 775 cm ^-1 .

MS (EI, 70 eV):
m / z (%) = 482 (0.5, M⁺), 425 (4, M⁺-tBu), 147 (82), 133 (46), 91 (29), 73 (100).

C₂₆H₅₄O₂Si₃ (482.96)
Calculated:
C 64.66, H 11.27;
found:
C 64.44, H 10.99.

Example 4 Bis [(dimethylisopropoxysilyl) methyl] zinc

1.02 g (42 mmol) magnesium shavings are baked in a 250 ml 2-necked flask with 3-way valve and dropping funnel below Overlay argon with some anhydrous THF. In the Dropping funnels are freshly distilled 7.20 ml (40 mmol) Chloromethyldimethylisopropoxysilane filled and with the same Diluted volume of THF. With vigorous stirring, approx. 5-10 Drops of the chlorosilane solution added to the magnesium and 2-3 Drop 1,2-dibromoethane to start the Grignard reaction facilitate. After the reaction has started (suddenly starting Warming, test with phenanthroline) is under ice cooling the remaining chlorosilane solution slowly added dropwise and at the same time the batch by adding another 66 ml of THF diluted so that the total volume is finally 80 ml. When the addition is complete, the ice bath is removed and the batch stirred at room temperature. A titration results after 10 h with benzyl alcohol against phenanthroline a turnover of 80%. Further stirring does not lead to an improvement in sales. According to 0.5 equivalents (16 mmol) are fresh from the titrated content molten zinc chloride as a solution in THF for easy dripped brown-gray, clear Grignard solution. The approach is going stirred overnight at room temperature. The only weak one pink coloring with phenanthroline as well as the only weak Show alkaline pH of a sample quenched with water the complete conversion (if necessary, some zinc chloride solution be added). In the oil pump vacuum concentrated clear solution to about ¼ of their volume and then mixed with 40 ml of hexane. The immediately failing Magnesium salts are suctioned off after stirring for one hour (G3 frit). The resulting, slightly yellowish cloudy solution becomes concentrated and then distilled in an oil pump vacuum. Man receives 2.93 g (45% based on the chlorosilane used) zinc organyl as a colorless clear liquid in the refrigerator  crystallized (bp 78-80 ° C at 1.1 Torr, mp. 29-30 ° C). in the In contrast to bis [(trimethylsilyl) methyl] zinc ignites this zinc organyl does not spontaneously enter the air but only smokes.

1 H-NMR (400 MHz, CDCl₃):
δ = -0.41 (s, Zn-CH₂-, 2H), 0.10 (s, Si (CH₃) ₂, 6H), 1.11 (d, J = 6.0 Hz, -CH (C H ₃) ₂, 6H), 3.95 (sept, J = 6.0 Hz, -C H (CH₃) ₂, 1H).

13 C-NMR (100 MHz, CDCl 3):
δ = 1.87 (Zn-CH₂-), 1.98 (Si (CH₃) ₂), 26.08 (-CH ( C H₃) ₂), 64.80 (- C H (CH₃) ₂).

Example 5 [aR] - [1- [4- (1,1-dimethylethyl) cyclohexylidene] ethyl] dimethyl isopropoxysilane

Analogously to that described in Example 2, 62 mg (0.2 mmol) of this sulfoximine with 0.4 mmol (132 mg) of bis [(dimethyl isopropoxysilyl) methyl] zinc with catalysis by NiCl₂dppp and 3 equivalents of MgBr₂ as a salt in 15 ml of anhydrous ether implemented. After 4 d, complete conversion can be demonstrated by thin layer chromatography. The clear orange-umbra colored solution is saturated with sat. Quenched NaHCO₃ solution, extracted with ethyl acetate (EA) / hexane 1:50 mixture and filtered after drying (MgSO₄) over silica gel (post-elution with EA / hexane 1:50 to separate the sulfinamide). After chromatography (FC, EA / hexane 1:50, R _f (product) = 0.44), 65 mg of product are obtained as a colorless oil. According to the GC, the purity is 85%. This corresponds to a yield of 96%. Even by considerable variation of the eluent, it was not possible to completely separate the contaminants by chromatography.

According to the 1 H-NMR shift spectrum, the ee value is in the presence of 2 equivalents Agfod / Pr (tfc) ₃ (see Example 2.) 95%. Here too, as with the allylsilanes described under 2 the signals of the silyl groups split. The methyl groups of the enantiomeric silanes appear as 2 Singlets at around -0.1 ppm (DD = 0.024 ppm), with the Singlets of the aR-configured silane appear in the higher field.

[α] = - 22.8, [α] = - 11.1 (c = 0.171, hexane)

1 H-NMR (400 MHz, CDCl₃):
δ = 0.08 (s, SiMe₂, 6H), 0.82 (s, t-Bu, 9H), 0.87-1.03 (m, 3-Ha, 5-Ha, 2H), 1.12 (tt, 4-H, 1H - signal partially superimposed), 1.13 (d, J = 6.2 Hz, O-CH- ( CH₃ ) ₂, 6H), 1.49 (d, J _8.7 = 8.4 Hz, 8-H, 2H), 1.51 (mt, J _{2a, 2e} = J _{2a, 3a} = 13.5 Hz, 2-Ha, 1H), 1.75-1.84 (m, 3-He, 5-He, 2H), 1.97 (mt, J _{6a, 6e} = J _{6a, 5a} = 13.5 Hz, 6-Ha, 1H), 2.18 (md, J _{6e, 6a} = 13.5 Hz, 6-He, 1H), 2.57 (md, J _{2e, 2a} = 13.5 Hz, 2-He, 1H), 3.97 (sept, J = 6.2 Hz, O- CH - (CH₃) ₂, 1H), 5.06 (mt, J _7.8 = 8.4 Hz, 7-H, 1H).

13 C-NMR (100 MHz, CDCl 3):
δ = -1.57 (Si ( C H₃) ₂), 18.16 (C-8), 25.88 (O-CH- ( C H₃) ₂), 27.72 (C ( C H₃) ₃) , 28.22 28.36 (C-3, C-5), 29.39 (C-2 or C-6), 32.54 ( C (CH₃) ₃), 37.29 (C-2 or C -6), 48.66 (C-4), 65.04 (O- C H- (CH₃) ₂), 115.32 (C-7), 137.68 (C-1).

IR (film):
2970, 1382, 1367, 1258, 1250, 1174, 1130, 1028, 884, 837, 822 cm⁻¹.

MS (EI, 70 eV):
m / z (%) = 282 (M⁺, 4), 117 (SiMe₂OiPr, 100), 75 (91), 57 (CMe₃⁺, 8), 41 (9).

C₁₇H₃₄OSi (282.53)
HRMS: calc. 282.2373, found. 282.2367.

Example 6 [4- (1,1-dimethylethyl) cyclohexylidene] -2-ethanol

62 mg (0.2 mmol) of the alkoxysilane obtained in Example 5 are taken up in 20 ml of a 1: 1 mixture of THF and methanol, and 40 mg (0.4 mmol) of finely ground KHCO₃ are added. After adding about 10 equivalents of 30% H₂O₂ solution, the mixture is heated under reflux. The reaction is complete after 3-4 h (TLC control). Unnecessary longer cooking leads to the increased formation of polar by-products and thus to a reduction in the yield. It is therefore better to add some H₂O₂ if necessary. For working up, about 10 ml of H₂O and an equal proportion of hexane are added for better phase separation. The organic phase is separated off and the aqueous phase is subsequently extracted with ether. The combined organic phases are dried over MgSO₄, concentrated and then chromatographed (FC, EA / hexane 1: 3, R _f (product) = 0.21). 29 mg (73%) of pure allyl alcohol are obtained as a colorless oil.

[α] = - 23.3, [α] = - 9.1 (c = 0.172, hexane)

1 H-NMR (400 MHz, CDCl₃):
δ = 0.85 (s, t-Bu, 9H), 0.99 (dq, J _{3a, 3e} = J _{3a, 2a} = J _{3a, 4} = 12.5 Hz, J _{3a, 2e} = 3.9 Hz , 3-Ha, 1H), 1.06 (dq, J _{5a, 5e} = J _{5a, 6a} = J _{5a, 4} = 12.5 Hz, J _{5a, 6e} = 3.9 Hz, 5-Ha, 1H) , 1.18 (tt, J _4.5a = J _4.3a = 12.5 Hz, J _4.5e = J _4.3e = 3.0 Hz, 4-H, 1H), 1.74 (mt, J _{2a, 2e} = J _{2a, 3a} = 13.5 Hz, 2-Ha, 1H), 1.83-1.91 (m, 3-He, 5-He, 2H), 2.04 (mt, J _{6a, 6e} = J _{6a, 5a} = 13.5 Hz, 6-Ha, 1H), 2.25 (md, J _{6e, 6a} = 13.5 Hz, 6-He, 1H), 2.69 (md, J _{2e, 2a} = 13.5 Hz, 2-He, 1H), 4.13 (md, J _8.7 = 6.8 Hz, 8-H, 2H), 5.35 (tt, J _7.8 = 6.8 Hz, J _7.6a = J _7.2a = 1.7 Hz, 7-H, 1H). The assignment was made by decoupling experiments.

13 C-NMR (100 MHz, CDCl 3):
δ = 27.67 (C ( C H₃) ₃), 28.61 28.73 (C-3, C-5), 29.10 (C-2 or C-6), 32.54 ( C (CH₃ ) ₃), 36.99 (C-2 or C-6), 48.37 (C-4), 58.75 (C-8), 119.99 (c-7), 144.58 (C- 1).

IR (film):
3320, 2930, 2850, 2830, 1665, 1475, 1438, 1387, 1358, 1235, 1220, 1065, 1005, 985 cm⁻¹.

MS (EI, 70 eV):
m / z (%) = 182 (M⁺, 2), 164 (12), 149 (6), 121 (13), 108 (19), 93 (32), 79 (37), 57 (t-Bu , 100), 41 (50).

C₁₂H₂₂O (182.30)
Calculated:
C 79.06, H 12.16;
found:
C 78.84, H 12.46.

HRMS: calc. 182.1665, found. 182.1660.

Example 7 [3aS- (2E, 3aα, 4α, 5β, 6aα)] - [[5 - [[(1,1-dimethylethyl) dimethyl silyl] oxy] -4 - [[[(1,1-dimethylethyl) dimethylsilyl] oxy] methyl] hexahydro-2 (1H) -pentalenylidene] ethyl] dimethyl isopropoxysilane

Analogous to that described in Example 3, 55 mg (0.1 mmol) of this sulfoximine with 0.2 mmol (66 mg) bis [(dimethylisopropoxysilyl) methyl] zinc with catalysis of 20 mol% NiCl₂dppp (11 mg) and 3 equivalents of MgBr₂ implemented as a salt in 10 ml of anhydrous ether. After 1 d the conversion was complete (TLC control), and the olive-green solution is quenched by adding saturated NaHCO₃ solution, extracted with hexane and filtered through a short silica gel column. After concentration of the filtrate and subsequent purification chromatography (FC, EA / hexane 1:50, R _f (product) = 0.38), 49 mg (92%) of pure "cross-coupling" product are obtained as a colorless oil. The E / Z selectivity is 99: 1 (GC).

[α] = 41.4, [α] = 10.4 (c = 0.222, hexane)

1 H-NMR (400 MHz, CDCl₃):
δ = -0.02, -0.01, 0.00 0.04, 0.08 (s, Si Me₂ i-Prop, Si Me₂ t-Bu, 18H), 0.85, 0.88 (SiMe₂ t -Bu , 18H), 1.14 (d, J = 6.2 Hz, i-Pr, 6H), 1.17 (m, 6-Hβ, 1H), 1.42 (m, 4-Hβ, 1H ), 1.48 (d, J1 ′, 2 ′ = 8.4 Hz, 1′-H, 2H), 1.98-2.42 (m, 1-Hβ, 3-Hβ, 6-Hα, 3a -H, 1-Hα, 6a-H, 3-Hα, 7H), 3.57 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 5.3 Hz, 7-H, 1H), 3.61 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 3.6 Hz, 7-H, 1H), 3.81 (dt, J _{5 a , 4 β} = 9.0 Hz, J _{5 α , 6 α} = 6.6 Hz, 5-Hα, 1H), 3.97 (quint, J = 6.2 Hz, i-Pr, 1H), 5.20 (mt, J _{2 ′, 1 ′} = 8.4 Hz). The assignment was made by decoupling experiments.

13 C-NMR (100 MHz, CDCl 3):
δ = -5.39 -5.28 -4.73 -4.37 -1.45 -1.43 (SiMe₂), 18.14 18.45 (SiMe₂ t-Bu ), 20.38 (C-1 ′), 25.89 (i-Pr), 25.96 26.07 (SiMe₂ t-Bu ), 35.66 39.73 42.45 (C-6, C-3, C-1), 38, 35 41.47 (C-3a, C-6a), 55.68 (C-4), 62.28 (C-7), 65.06 (i-Pr), 74.08 (C-5), 115.60 (c-2 ′), 141.07 (C-2).

IR (film):
2966, 2935, 2898, 2861, 1474, 1465, 1259, 1120, 1031, 886, 839, 777 cm⁻¹.

MS (EI, 70 eV):
m / z (%) = 527 (M⁺, 3), 470 (M⁺- t-Bu, 8), 337 (5), 263 (24), 209 (32), 147 (100), 117 (SiMe₂ -O-iPr, 100), 75 (100), 59 (22).

C₂₈H₅₈O₃Si₃ (527.0)
Calculated:
C 63.81, H 11.09;
found:
C 63.56, H 10.94.

Example 8 [3aS- (2E, 3aα, 4α, 5β, 6aα)] - [5 - [[(1,1-dimethylethyl) dimethyl silyl] oxy] -4 - [[[(1,1-dimethylethyl) dimethylsilyl] oxy] methyl] hexahydro-2 (1H) -pentalenylidene] -2-ethanol

Analogously to the oxidative cleavage described in Example 6, 45 mg (0.085 mmol) of the bicyclic allylsilane obtained in Example 7 are taken up in 10 ml of a 1: 1 mixture of THF and methanol, and 17 mg (0.17 mmol) of finely ground KHCO₃ are added . After adding about 10 equivalents of 30% H₂O₂ solution, the mixture is heated under reflux. After 5 h, only traces of starting material can be detected using thin layer chromatography. After analogous work-up (see Example 6) and subsequent chromatography (FC, EA / hexane 1:50 1: 1, R _f (product) = 0.58 (1: 1)), 25 mg (69%) of pure product are obtained.

[α] = - 14.8, [α] = - 6.0 (c = 0.420, hexane)

1 H-NMR (400 MHz, CDCl₃):
δ = 0.00-0.02 (m, Si Me₂ t-Bu, 12H), 0.85, 0.87 (s, SiMe₂ t-Bu , 18H), 1.19 (m, 6-Hβ, 1H ), 1.44 (m, 4-Hβ, 1H), 2.06-2.25, 2.32-2.49 (m, 1-H, 3-H, 3a-Hα, 6a-Hα, 7H ), 3.57 (dd, J _gem = 10.0 Hz, J _{7.4 β} = 5.3 Hz, 7-H, 1H), 3.60 (dd, J _gem = 10.0 Hz, J _{7 , 4 β} = 3.8 Hz, 7-H, 1H), 3.84 (dt, J = 9 Hz, J = 6.8 Hz, 5-Hα, 1H), 4.09 (m, 1′- H, 2H), 5.47 (mt, J = 6.5 Hz, 2′-H, 1H).

13 C-NMR (100 MHz, CDCl 3):
δ = -5.42 -5.30 -4.74 -4.41 (Si Me₂ t-Bu), 18.15 18.42 (SiMe₂ t-Bu ), 25.95 26.05 (SiMe₂ t-Bu ), 35.48 39.75 42.28 (C-6, C-3, C-1), 38.37 41.02 (C-3a, C-6a), 55.79 (c-4), 60.84 (C-1 ′), 62.18 (C-7), 74.04 (C-5), 120.24 (C-2 ′), 147.38 (C-2).

MS (EI, 70 eV):
m / z (%) = 369 (M⁺- t-Bu, 2), 351 (8), 145 (100), 133 (18), 119 (36), 105 (21), 91 (37), 73 (77), 67 (17), 59 (14).

MS (CI, ammonia):
m / z (%) = 444 (M + NH₄⁺, 45), 427 (MH⁺, 14), 409 (M-OH⁺, 25), 145 (17), 132 (HO-SiMe₂t-Bu] ⁺, 100).

C₂₃H₄₆O₃Si₂ (426.8)
Calculated:
C 64.73, H 10.86;
found:
C 64.54, H 10.77.

Example 9 [3aS- (2E, 3aα, 4α, 5β, 6aα)] - [5 - [[(1,1-dimethylethyl) dimethyl silyl] oxy] -4 - [[[(1,1-dimethylethyl) dimethylsilyl] oxy] methyl] hexahydro-2 (1H) -pentalenylidene] -2-ethoxy-acetic acid- 1,1-dimethylethyl ester

25 mg (0.059 mmol) of the allyl alcohol obtained in Example 8 and 238 mg (0.19 ml, 1.2 mmol) of 1-bromoacetic acid t-butyl ester and 20 mg (0.059 mmol) of tetrabutylammonium hydrogen sulfate (PTC) are added in 0.5 ml Methylene chloride added. After adding 1 ml of 50% aqueous NaOH solution, the mixture is stirred for 2 d at room temperature. Then, starting material was no longer detectable by means of thin layer chromatography. For working up, a little water is added and extracted with ether. The combined ether phases are dried over MgSO₄, concentrated on a rotary evaporator and then chromatographed (FC, LM EE / hexane 1:10, R _f (educt) = 0.12, R _f (product) = 0.41). 23 mg (74%) of pure product are obtained as a colorless oil.

1 H-NMR (400 MHz, CDCl₃):
δ = 0.00, 0.01, 0.02 (s, Si Me₂ t-Bu, 12H), 0.84, 0.86 (s, SiMe₂ t-Bu , 18H), 1.19 (m, 6 -Hβ, 1H), 1.46 (m, 4-Hβ, 1H), 1.47 (s, Ot-Bu, 9H), 2.05-2.25, 2.30-2.51 (m, 1-H, 3-H, 3a-Hα, 6a-Hα, 6-Hα, 7H), 3.56 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 5.3 Hz, 7- H, 1H), 3.60 (dd, J _gem = 10.2 Hz, J _{7.4 β} = 3.6 Hz, 7-H, 1H), 3.84 (dt, J = 9 Hz, J = 6.8 Hz, 5-Hα, 1H), 3.92 (d, J = 1.2 Hz, C H ₂COOt-Bu, 2H), 4.05 (d, J _{1 ′, 2 ′} = 7.0 Hz, 1′-H, 2H), 5.41 (mt, J _{2 ′, 1 ′} = 7.0 Hz, 2′-H, 1H).

13 C-NMR (100 MHz, CDCl 3):
δ = -5.42 -5.30 -4.75 -4.40 (Si Me₂ t-Bu), 18.13 18.42 (SiMe₂ t-Bu ), 25.95 26.05 (SiMe₂ t-Bu ), 28.21 (CO₂ t-Bu ), 35.70 39.78 42.22 (C-1, C-3, C-6), 38.47 41.07 (C-3a, C-6a) , 55.82 (C-4), 62.16 (C-7), 67.38 ( C H₂-CO₂t-Bu), 68.79 (C-1 ′), 74.06 (C-5), 81.46 (CO₂ t-Bu ), 116.79 (C-2 ′), 149.26 (C-2), 169.99 ( C O₂t-Bu).

MS (EI, 70 eV):
m / z (%) = 351 (6), 175 (15), 145 (52), 133 (17), 117 (14), 105 (10), 91 (18), 73 (31), 57 (t -Bu⁺, 100), 41 (29).

MS (CI, methane):
m / z (%) = 409 (M-OSiMe₂t-Bu] ⁺, 6), 351 (6), 277 (27), 145 (100), 133 (66), 77 (25).

C₂₉H₅₆O₅Si₂ (540.9)
Calculated:
C 64.39, H 10.44;
found:
C 64.37, H 10.24.

Claims (3)

1. Allylsilane derivatives of the formula I. wherein
R¹ and R² together form a bond or the rest where R⁹ represents a C₁-C₁₀ alkyl radical,
R³ and R⁴ are identical or different and are hydrogen, C₁-C₁₀-alkyl, C₅-C₇-cycloalkyl, C₁-C₆-alkoxy, C₆-C₁₀-aryl, C₇-C₁₂-aralkyl or, if R¹ and R² together represent a bond, R³ and R⁴ together represent a substituted propylene radical,
R⁵ is hydrogen or a C₁-C₂₀-alkyl, C₂-C₂ Hydrox-alkenyl or C₂-C₂₀-alkynyl group which is optionally substituted by a free or protected amino group, methylamino, hydroxy, carboxy, mercapto or halogen, which may be replaced by -O-, - S-, -NH- or -N (CH₃) - can be interrupted,
represents and
R⁶, R⁷, R⁸ are the same or different and are C₁-C₄-alkyl, C₁-C₄-alkoxy or phenyl. 2. Process for the preparation of allylsilane derivatives of the formula I. wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have the meanings given in claim 1, characterized in that a phenylsulfoximine derivative of the formula II wherein R¹, R², R³, R⁴ and R⁵ have the meanings given in claim 1 and R¹⁰ is C₁-C₄-alkyl or p-toluenesulfonyl, optionally after protecting free OH groups with an organozinc compound of the formula IIIZn (CH₂SiR⁶R⁷R⁸) ₂ (III ) wherein R⁶, R⁷ and R⁸ have the meanings given in claim 1, with catalysis with NiCl₂ · (C₆H₅) ₂P (CH₂) ₃P (C₆H₅) ₂ and with the addition of a lithium, magnesium or zinc salt. 3. Zinc compounds of the general formula IV Zn (CH₂SiR⁶R⁷R¹⁷) ₂ (IV) where R¹⁷ must be a C₁-C₄ alkoxy group.