MXPA00008540A

MXPA00008540A - Method for stereochemically controlled production of isomerically pure highly substituted azacyclic compounds

Info

Publication number: MXPA00008540A
Application number: MXPA/A/2000/008540A
Authority: MX
Inventors: Michael Reggelin; Timo Heinrich; Bernd Junker; Antel Jochen; Ulf Preuschoff
Original assignee: Solvay Pharmaceuticals Gmbh
Priority date: 1998-05-13
Filing date: 2000-08-31
Publication date: 2001-07-09

Abstract

The invention relates to a method for stereochemically controlled production of azacyclic compounds of general formula (I), whereby the substituents have the meaning cited in the description. The invention also relates to intermediate products of this method and to novel azacyclenes.

Description

METHOD FOR PRODUCTION ESTEREOQUIMI CAMENTE CONTROLLED COMPONENTS OF AZAC ICES REPLACED IN HIGH DEGREE, PURE AS ABOUT THE ISOMERS DESCRIPTION OF THE INVENTION The present invention concerns a new process for the stereochemically controlled preparation of new and known azacyclic compounds substituted in a high degree, as well as intermediates of this process. In addition, the invention concerns novel azacyclic compounds whose isomers are highly pure, in terms of isomers, which have useful properties for numerous applications. High-substituted stereoisomers of azacyclic compounds, especially high-substituted derivatives of pyrrolidines or piperidines, are useful starting materials for numerous applications and find use, for example, as constituents of chiral catalysts in asymmetric synthesis (see for example Kobayashi et al. , Chemistry Letters (= Chem. Lett.) (1991) 1341-1 344), as constituents of biologically active alkaloids (see for example Williams et al., Journal of Organic Chemistry (= JOC) 57 (1992 6,527-6,532 and the references cited in that bibliographic citation, Jager et al., Ange andte Chemie 102 (1990) 1180-1,182) and as constituting pharmacologically and interesting compounds (see, for example, Laschat et al., Synthesis 4_ ( 1997) 475-479). In addition, those of cahi dr or -quinolines and pyrrolidines which can be prepared, for example, according to the process according to the invention have interesting physiological effects (see, for example, Kuzmits ii and collaborated, Vestsi Akad, Navuk BSSR, Ser. Khim. Navuk 3_ (1979) 82-85) / Chemical Abstracts No. 91: 117158c; Lash et al., Journal of Heterocyclic Chemistry 2_8_ (1991) 1671-1676). The use of the pyrrolidines mentioned above for the preparation of cyclic porphyrin systems is also discussed in these citations. From the bibliographical references indicated, procedures for the preparation of such azacyclic compounds are also known in part. Certain enantiomers of these compounds can be obtained according to the methods there usually indicated by conventional separation of racemates. However, methods of preparation which are not according to the invention are also described, according to which the pure individual compounds selected from substituted azacycles can be prepared in their pure state. A general procedure for the synthetic synthesis of the high-substituted azacycles, pure as isomers, is not known on the contrary from the bibliographical references mentioned above. In addition, the stereo-controlled synthesis of some tetrahydrofuran substituted, isomers-pure derivatives, from 2-to-1-quenil-s-oximines and aldehydes is already known (see Reggelin et al., JACS 118 (1996) 4,765). -4.777; Reggelin et al. *, Liebigs Annalen der Chemie / RECUEIL (1997) 1881-1.886). However, azacyclic compounds can not be prepared according to the process described therein. From the publication on the Internet at the address "www.iucr.ac.uk" of M. Bolte, Acta C rysta 11 ogr aph ica Section C, article published electronically QA0017 [= (IUCr) Minutes C Paper QA 0017 the compound (2S, 3S, 4S, 5S) - (N-tert-butyl-oxycarbonyl) -2-benzyl-4,5-dimethyl-3-hydroxypropyl idine is already known. The preparation of this compound is not described in the indicated publication. It was the object of the present invention to provide a method for the controlled preparation of eoquimely new and known azacyclic compounds that are highly substituted, pure in the isomers, whereby the type and number of substituents in these compounds. further, it was the object of the present invention to make available novel azacyclic compounds, which are highly pure, in terms of isomers, for numerous sectors of applications. It has surprisingly been found that high-grade azacyclic compounds, which are pure in terms of isomers, can be obtained in good yield, in which the type and number of the substituents can be varied widely, if, according to an Known process, metallated 2-alkenyl sulfo-pyrimidine compounds are reacted with N-protected amide derivatives. Accordingly, a process for the controlled preparation is thermochemically of compounds of the invention. General I, wherein n means 0 or 1, R1 means hydrogen, Ci-Cß alkyl, or phenyl-Ci-Cß alkyl optionally substituted once or multiple times on the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or haloalkoxy lower, and R 2 signifies hydrogen, or R 1 and R 2 together mean a doubly linked methylene group, which may be substituted with C 1 -C 5 alkyl, or with phenyl-C 1 -C 5 alkyl optionally substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy, R3- denotes hydrogen, and R signifies hydrogen, lower alkyl, or phenyl-lower alkyl and is substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy, or R3 and R4 also mean in common a C2 alkylene chain or a C3-C6 alkylene chain optionally containing from 1 to 3 double bonds, which may be dotted with a C?-C al alkylene optionally substituted once or twice with lower alkyl, R 5 signified hydrogen, lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkyl or phenyl-lower alkoxy and are each substituted once or multiple times in the phenyl ring with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy, and R6 signifies hydrogen, and R7 signifies hydrogen, and R8 signifies hydrogen, cyano, carboxy and esterified ester, ca rbon i 1-amino and once or twice substituted in the nitrogen, a system of; rings, monocyclic or bicyclic, with 3 to 10 ring carbon atoms, optionally introduced once or multiple times, whose ring carbon atoms may be replaced once or multiple times by nitrogen, oxygen and / or sulfur, and whose system The ring can be substituted once or multiple times with lower alkyl, halo lower alkyl, lower alkoxy, hydroxy, halogen or with a lower alkylene chain, which is attached to two oxygen atoms attached to adjacent carbon atoms of the rings, or may also represent linear or branched C1-C12 alkyl, optionally containing one or more double bonds, which may be substituted once or multiple times with halogen, hydroxy, lower alkoxy, optionally esterified carboxy, cyano, mercapto, alkyl lower - thio, amino, lower alkyl - ami no, ca rboni 1 - ami not optionally substituted once or twice in the nitrogen, a ring system , monocyclic or bicyclic, with 3 to 10 ring carbon atoms, optionally unsaturated once or multiple times, whose ring carbon atoms may be replaced once or multiple times by nitrogen, oxygen and / or sulfur, and whose rings may be substituted once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, halogen, or with a lower alkylene chain, which is attached to two oxygen atoms attached to adjacent carbon atoms of the rings, oco R and R can also form, in common with the carbon atoms, to which they are attached, a ring system, monocyclic or bicyclic, with 5 to 10 carbon atoms of ring, which optionally contains 1 to 3 double bonds, whose carbon atoms not bearing the substituents R5 or R8 can be replaced once or multiple times by sulfur, oxygen and / or nitrogen, and which can be replaced once or multiply once. three times with lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, hydroxy, halogen or with a lower alkylene chain, which is attached to two oxygen atoms attached to adjacent carbon atoms of the ring system, or R can also • form a bond in common and R5 and R8 can form in common with the carbon atoms, to which they are attached, an aromatic ring system, which can be fused with another 2 to 4 carbon atoms to form a bicyclic ring system, which in total contains 8 to 10 carbon atoms of rings, which has a total of 3 to 5 double bonds, carbon atoms that are not carrying the substituents R5 and R8 of this ring system from C6 to C? to be replaced once or multiple times by sulfur, oxygen and / or nitrogen, and this ring system from Ce to C? 0 being able to be substituted once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy, halo -lower alkoxy, hydroxy, halogen, or with a lower alkylene chain that is attached to two oxygen atoms attached to adjacent carbon atoms of the ring system, means hydrogen, lower alkyl, phenyl-lower alkyl optionally substituted on the ring of phenyl once or multiple times with lower alkyl, halo lower alkyl, lower alkoxy or halo lower alkoxy, or means an amino protecting group, or R7 and R9 may also form in common a C3-C / e Y alkylene chain S.I.G Nigegen or NH, and their salts by addition of acids, can be reactive groups, possibly present in compounds of Formula I, be blocked by appropriate protecting groups, characterized in that a) for the preparation of a compound of the general Formula II , wherein R3 and R4 have the above meanings, R101 has the meaning indicated above for R1 except for a substituted methylene group and Ar represents phenyl optionally substituted once or multiple times with lower alkyl, R10 means lower alkyl, or phenyl optionally substituted on the phenyl ring once with lower alkyl or with hydroxy, which is protected by an appropriate protecting group, or means phenyl-lower alkyl optionally substituted on the phenyl ring once on lower alkyl , and R1101 represents a silyl protecting group, aa) a stereoisomer of a compound of general Formula III is reacted, wherein Ar and R10 have the above meanings, with a compound of general Formula IV, wherein R101 and R4 have the above meanings and M1 represents a univalent group, which contains an alkali metal or an alkaline earth metal and a halogen atom, and is blocked with a silyl protecting group R1101 a hydroxyl group which is optionally freedom in this reaction, to obtain a compound of the general formula lia, wherein R101, R4 R10 R1101 and Ar have the meanings mentioned above, or abl a stereoisomer of a compound of the general Formula V wherein R, 1i0U R UJ- * and Ar possess the above meanings, is deprotonated with an appropriate base for its deprotonation, the deprotonated compound of Formula V is reacted with a compound of general Formula VI, wherein a means methylene or means a C2-Cs alkylene chain, which may optionally be dotted with C? -C2 alkylene optionally substituted once or twice with lower alkyl, and the intermediate product obtained is treated sequentially with a reagent which makes possible the separation of the oxygen atom that comes from the carbonyl group of the compound of the Formula VI and with one of the bases mentioned above, which is appropriate for the deprotonation of a compound of the Formula V, to obtain a compound of the formula General Ilb, wherein R 101, 10 1101 Ar and possess the above meanings, or ab2) a compound of general Formula XII, in which a has the above meaning, it is treated with a reagent appropriate for its lithium-containing base and the resultant lithiated and de-selenized intermediate is reacted with a stereoisomer of a compound of the Formula III, to obtain a compound of the Formula Ilb, and the compounds obtained of the Formula II, wherein R101 signifies hydrogen, are alkylated if desired by deprotonation with an appropriate base therefor and by subsequent reaction with a compound of the Formula General XI, 103 XI wherein R103 has the indicated meaning for R101 with the exception of hydrogen and Z represents a separable leaving group, b) a compound of Formula II is consecutively reacted with an appropriate base for deprotonation, with an organometallic reagent of the Formula General VII, X '(OR12) VII wherein X represents halogen, M means a quadrivalent transition metal and R12 represents lower alkyl, phenyl or phenyl-lower alkyl, and. with a stereoisomer of a compound of general Formula VIII, * * * * 1 i n0 * * * in which R5, Rd, R7 and n have the above meanings, R801 has the meaning of R8, the possible reactive groups being, if necessary, blocked by stable protective groups against bases, R represents hydrogen in common with R801, a C-C4 alkylene chain, and R13 means an unstable protecting group against bases, to form, a stereoisomer of a compound of the general Formula IX, where R, 101 R ° R '801 R 901 R 1i0U, 12 13 R, ", RJ n Ar M2) have the above meanings, c) the compound obtained of Formula IX is transformed, by treatment with an appropriate base for the elimination of the R13 group, into a compound of the Formula General Xa, *** .lb *** where R101, R3, R4, R5, R6, R6, R7, R801, R901 R10 R1101 n and Ar have the above meanings, if R901 represents hydrogen, the nitrogen atom in the cyclic fundamental network of the resulting compound of the Formula is blocked. Xa with a stable protecting group against bases, and d) for the preparation of a compound of the general formula wherein R1, R2, R3, R4, R5, R6, R7 R801 and n possess the above meanings, and R9 2 represents a stable protecting group against bases or, in common with R801, a C3-C alkylene chain, gives ) a compound obtained from Formula Xa is reacted with a suitable reagent for cleavage by "reduction of the bond" -az-uf alkyl, to obtain a compound of the general Formula Ib wherein R101, R3, R4, R5 R6 R7 R801 R902 and n have the above meanings, or db) in a compound obtained of Formula Xa, wherein R101 does not represent hydrogen, the sulfur-alkyl bond is unfolded after electrophilic activation of the s-onimidoyl unit or, under the conditions of a base-induced elimination, to obtain a compound of the general Formula I, wherein R3, R4, R5, R6, R7, R801 R902 and n have the above meanings and R102 represents C1-C5 alkyl, or phenyl-lower alkyl optionally substituted once or multiple times in the phenyl ring with lower alkyl, halo lower alkyl, lower alkoxy or lower haloalkoxy, whose lower alkylene chain can contain from 1 to 5 carbon atoms, and a compound obtained from the Formula is reacted as desired once or multiple times by chemical conversion, in each case mediating inversion of the configuration at the ring carbon atom at position 3 of the compounds of Formula la, with a nucleophilic reagent suitable for the renewed generation of an OH group or for the generation of an NH2 group in position 3, and / or if desired the possible protective groups existing in compounds of the formula are again separated, and if desired the NH group optionally released, in position 1 of The basic cyclic screen is reacted with a reagent capable of N-alkylation or with a reagent capable of forming amides, or blocked with an amino-protecting group, and / or compounds of Formula la, or compounds obtained from of these compounds by the above-mentioned nucleophilic substitution reactions, which take place under inversion, are reacted, if desired, to form salts by addition of acids, in order to obtain compounds of the formula I. In addition, new azacyclic compounds are the object of the invention. . If, in compounds of Formula I or in other compounds described in the context of the present invention, the substituents mean or contain lower alkyl, it may be branched or unbranched and usually contain from 1 to 4 carbon atoms. If in the definitions of the substituents of compounds of Formula I or Formula X these constituents of substituents, for example radicals attached to phenyl rings, can be contained once or multiple times, these can usually be contained from once. up to three times. If in compounds of the present invention one or several carbon atoms can be replaced by heteroatoms such as oxygen, sulfur or nitroger, they can usually be replaced by heteroatoms of one to three carbon atoms. Preferably, a carbon atom can be replaced by a heteroatom. If certain substituents can contain one or more double bonds, the cyclic substituents, depending on the size of the ring, can usually contain 1-4 double bonds and can preferably form aromatic systems. The aliphatic substituents may contain, for example, 1 to 3 double bonds. Preferably, the compounds of Formula I can be prepared in the pure state as regards the isomers., where R4 does not mean hydrogen. If R4 has a meaning other than hydrogen, the ring closure reaction to form compounds of Formula Xa in step c) of the process proceeds with an especially high selectivity, and the compounds of Formula Ia and Formula I, obtained The compounds of the Formula Xa can be obtained with a particularly small proportion of byproducts. If R and R4 together represent a C3-C6 alkylene chain optionally bridged, the alkylene chain may preferably contain from 3 to 4 carbon atoms. If the alkylene chain is bridged, the bridging chain may preferably possess 1 carbon atom, which may preferably be substituted with lower dialkyl. Especially R3 and R4, in common with the carbon atoms to which they are attached, can form the system of 7,7-dimethyl-bicyclo [3.1.1] heptane. If the substituent R8 means or contains optionally esterified carboxy, the carboxyl group can be esterified with conventional alcohols, not sterically hindered, for example with linear or branched cycloaliphatic or cyclic aliphatic alcohols which optionally contain one or more double bonds, alcohols may optionally be substituted once or multiple times with halogen or lower alkoxy, or may also be esterified with phenyl- (lower alkyl) alcohols optionally substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or lower haloalkoxy. If R8 means or contains 1-aminocarbonyl optionally substituted once or twice in the nitrogen, the amino group contained therein may be substituted, for example, once with C3-Cs cycloalkyl 1 to 1 or less. or straight or branched aliphatic Ci-Ce alkanoyl, which may optionally be substituted once or multiply with halogen or lower alkoxy, optionally substituted on the phenyl ring one or more times or more times with lower alkyl, halo-lower alkyl, lower alkoxy or lower haloalkoxy, or the amino group may be substituted eg also once or twice with C3-C8-alkylalkyl or lower alkyl or C6-C6 aliphatic alkyl linear or branched, which can be substituted once or multiple times with halogen or lower alkoxy, phenyl-lower alkyl optionally substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl lower, lower alkoxy or halo-lower alkoxy, or the amino group may be protected for example with an appropriate amino protecting group. If R8 means or contains a ring system, monocyclic or bicyclic, usually substituted with 3 to 10 carbon atoms, this may represent, for example, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, p-bromophenyl or 3-indolyl. Suitable protecting groups, which can be used in the compounds indicated within the framework of the present invention, are known, for example, from the McOmie works, "Protective Groups in Organic Chemistry", Plenum Press, or Green, Wuts , "Protective Groups in Organic Synthesis", Wiley Interscience Publication. The reaction of a stereoisomer of cyclicallysulphized s of the Formula III with a metallated alkene of Formula IV in step aa) of the process to form a 2-alkenyl sulphoximide of Formula II, pure as to the isomers, can be carried out in a polar or weakly polar aprotic solvent, inert under the reaction conditions, for example in the lower alkyl (cyclic or open chain) ethers such as diethyl ether ( = ether) or tetrahydrofuran (= THF), in the case of polyethylene glycol-low molecular weight esters such as di eti 1 engl1 co 1 -dime ti 1-é t er (= diglyme) or substituted benzenes such as toluene or xylene. Preferably THF can be used. The reaction can be carried out by mixing the reactants at a temperature of from -100 ° C to -50 ° C., preferably at -78 ° C, in one of the solvents indicated above, and reacting the resulting reaction mixture briefly, for example for 2 to 10 minutes, at the indicated temperature, and then letting it warm to a higher temperature below room temperature, preferably at -20 ° C to 0 ° C. If necessary, in order to complete the reaction, stirring may continue for some time at -20 ° C to 0 ° C. It is advantageous to employ the compound of Formula IV in amounts greater than those in which it is available. For example, 1.5-2.5 moles of a compound of Formula IV can be reacted with one mole of a compound of Formula III. In the cyclic s olumes of Formula III, Ar may preferably represent p-tolyl. R can be especially methyl, isopropyl, isobutyl or phenyl, and preferably represents isopropyl. In order to achieve a desired controlled preparation of the compounds of Formula I, the sulfonimidates of Formula III should be used in pure form with respect to the isomers. By the expression "pure in terms of isomers", an excess between isomers (= excess between enantiomers, "ee", or excess between diastereoisomers, "de") of at least 95% is to be understood within the framework of the present invention. a pure isomer. In the formulas indicated within the framework of the present invention the sign "*" (asterisk) designates in each case a center of chirality, which is usually formed in a pure state as regards the isomers or which comes from ducts usually used in the pure state in regarding the isomers. If, for the preparation of compounds of the Formula I, starting compounds which are not pure in terms of the isomers, for example racemic, are used according to the preparation process according to the invention, mixtures of compound isomers can also be obtained naturally. of formula I. If they are used s ul f onimi dats of Formula III, in which the chiral sulfur atom and the chiral carbon atom carrying the R10 substituent present different absolute configurations (ie when, for example, the sulfur atom possesses configuration R and the carbon atom carrying the substituent R10 presents configuration S), particularly good results are obtained in relation to the stereochemical purity of the products of the formula I. They can be used especially as compounds of Formula III (Rs) - 4 (S) - is op r op i 1 - 2 - p - to 1 i 1 - 4, 5 - dihydro - [1, 2? 6, 3] oxat iazol - 2 - oxide and (SS) - (4R) -i s opropi 1 -2 -p-t ol i 1-4, 5 -dihydr or - [1,2-6,3] oxathiazole-2-oxide. The expressions Rs and Ss designate in each case the absolute configuration in the chiral sulfur atom. The only ones of the Formula III are known, for example, from the citation of Reggelin et al., Tetrahedron Letters (= TL) 33 (1992) 6,959-6,962 or. Reggelin et al. TL 3_6 (1995) 5,885-5,886, and can be prepared in a pure state as regards isomers according to the procedures indicated in each case or procedures analogous thereto. In the metallated compounds of Formula IV, the univalent group M 1 may mean a group containing an alkali metal, preferably lithium, or a group containing an alkaline earth metal and additionally a halogen atom. As the alkaline earth metal, magnesium is preferred. "As halogen, chlorine, bromine or iodine can be used, especially as the metallated compounds of the formula IV, it is possible to use alkenyl compounds which are known per se or known organic alkenyl compounds or compounds such as reagents of the quen 1 - Gr i gna rd Usually a hydroxyl group, which is released during the reaction of compounds of the formula III with compounds of the formula IV to form compounds of the formula, is blocked with an appropriate protecting group or R 1101 silyl in order to prevent unwanted consequential reactions. As the silyl protecting group R 1101 in compounds of the Formula Ia, trimethylsilyl (= TMS) can preferably be used. The order of succession of the reactions indicated in step ab) for the preparation of cycloalkyl compounds can be conveniently carried out as a sequence of reactions in a single vessel. . The reaction of a stereoisomer of a methylsulf oximine of Formula V with an appropriate base for its deprotonation, as well as the subsequent reaction steps: reaction of the deprotonated compound of Formula V with a compound of Formula VI, treatment of the obtained intermediate with a reagent, which makes possible the separation of the oxygen atom that comes from the carbonyl group of the compound of Formula VI, and treatment with one of the bases indicated above, are known per se and can be carried out according to a process reported in Reggelin et al., JACS 118 (1996) 4,765-4.777, or an analog thereof. The group Ar as well as the substituent R10 in compounds of the formula V may possess the preferred meanings indicated above for compounds of the formula III. As the silyl protecting group R1101 in compounds of the formula V, ter-bu t i 1-dime t i 1 -s i 1 i 1 o- (= TBS) can be preferably used. Analogously to the preferred stereochemical characteristics, indicated above for the compounds of the Formula Til, [Ss, N (1 S)] -N-E 1 - [[tert-butyl-dimethyl] can be used as compounds of Formula V -silylyl) oxy] methyl] -2-methyl-propyl] - S -me ti 1 - S - (4 -methyl-1-phenyl) -subf oximine and the [RS, (IR)] -N- [1- [[tert-butyl-dimethyl-silyl] oxy] -methyl] -2-methyl-p r op i 1] - S -me ti 1 - S - (4 -me ti 1 - f eni 1) - s ul f oximine. As the bases for the deprotonation of compounds of Formula V, for example, lower alkylated lithiated compounds such as n-butyllithium are suitable. As reagents, which make possible the separation of oxygen atoms originating from the carbonyl group of compounds of Formula VI, compounds are suitable, which in common with oxygen atoms form good labile groups from aliphatic radicals. Examples of such compounds which form good labile groups are, for example, esters or halides of sulphonic acids such as avid p-to-1-aluminum chloride, aluminum chloride, aluminum chloride, chloride trifluoric acid ome t-anophysic acid, methyl ester of trifluoric acid 1 ome t of ul phonic acid (= methyl triflate) or ester trimeti 1 - if 1 i 1 of acid trif 1 uo r ome ta non-sulphonic (= triflate of TMS). Preferably, TMS triflate can be employed. The compounds of the general Formula VI are known. For example, the open t anon a, c i c 1 hexanone or nopinone can be used as compounds of Formula VI. If bridged cyclic ketones are used as compounds of Formula VI, it is advantageous that the bridging alkylene chain is attached to at least one carbon atom that is located at position a to the carbonyl group. In this way, the reaction products are always formed by controlling the controlled environment. The preparation of compounds of formula I Ib by reaction of compounds of formula XII with compounds of formula III can be carried out in step ab2) of the process in a manner known per se, for example according to the method indicated in the publication of Reggelin et al., JACS 118 (1996) 4,765-4.777, for the preparation of cycloalkenyl sulphoximide compounds. , to which is expressly referred to herein. As allyl alcohol, which can be used for the preparation of selenium compounds of Formula XII, for example, mirtenol is suitable. In a variant of the invention compounds of the formula II can be prepared, in which R101 has a meaning other than hydrogen, by simply rotating compounds of the formula II, in which R101 represents hydrogen and then by alkylating them by reaction with a compound of Formula XI. As the bases for a previously mentioned deprotonation, suitable, for example, lower alkyl compounds such as n -bu t i 1-1 i t i o are suitable. A halogen, preferably bromine or chlorine, can be used as a separable leaving group Z in compounds of formula XI. The reaction can be carried out under the usual reaction conditions for this type of reactions. The deprotonation of compounds of Formula II with appropriate bases and the reaction of the autoflowed compounds of Formula II with organometallic reagents of Formula VII and then with the amino acids of Formula VIII to form the Compounds of Formula IX in step b) of the process can be carried out in an aprotic solvent - diol, previously indicated for the reaction of compounds of Formula III with compounds of the Formula IV. Preferably, weakly polar solvents such as substituted benzenes, especially toluene, can be used. Advantageously, the reaction can be carried out as a "reaction in a single vessel" by deprotonating a 2-alkenyl sulphoximide of the formula II, pure as regards the isomers, in a suitable solvent mentioned above at a low temperature, example between -100 ° C and -50 ° C, preferably at -78 ° C, for about 5 to 30 minutes, with an appropriate base, tran smete the proton form of the compound of Formula II at a temperature slightly elevated, for example between -20 ° C and 10 ° C, preferably at 0 ° C, with an organometallic reagent of the Formula VII, and then reacting again the intermediate product obtained, at a low temperature, for example between -100 ° C and -50 ° C, preferably at -78 ° C, with an N-protected amino-aldehyde of Formula VIII. As the bases for the deprotonation of compounds of the Formula II, preferably lithiated lower alkyl compounds such as n-butyllithium are preferably used. Usually, the base can be used in a small excess, for example in the molar ratio of from about 1: 1.05 to about 1: 1.20, based on the amount of the compound used in Formula II. In the organometallic reagents of Formula VII, X may represent a halogen, preferably chlorine. As the quadrivalent transition metal M2, titanium can preferably be used. Suitable substituents R12 are, for example, branched and unbranched lower alkyl groups, preferably isopropyl. Particularly preferably, it is possible to use cl or r o -t r i s (i s op r op o x i) t i t a i o as a compound of Formula VII. The organometallic reagent is advantageously used in a small excess, for example in the molar ratio of from about 1: 1 to 1.3: 1, based on the amount of the compound of Formula II used. The compounds of Formula VIII constitute protected chiral α- or β-amino-to-1 and can preferably be used in the pure state as regards isomers.

As protecting groups R13 which are unstable with respect to bases, the protective groups are adapted which, when carrying out their separation, generate a nucleophilic nitrogen atom in compounds of Formula VIII. Preferably, the protecting group ~ f 1 or r en-9-i 1 -me t i 1 - or x i -carbonyl (= FMOC) can be used as the group R 13. Other amino protecting groups can also be used, but the separation of the protecting group R and the ring-closure reaction can preferably be carried out in a single reaction step, provided that FMOC is used as the protective group. In the starting compounds of Formula VIII, the substituent R801 has the indicated meaning for R8, but it is verified that the reactive groups, if any, contained in the substituent R8, for example hydroxy, amino, mercapto or carboxy, are in each case blocked by stable protecting groups against bases, known per se, for example stable protecting groups against non-nucleophilic bases such as pyridine, in order to avoid undesired side reactions. The amino-a-1 -s of the formula VIII, pure in the isomers, are known or can be prepared in known manner from known compounds. Thus, for example, the aldehydes of Formula VIII can be obtained by means of moderate oxidation processes known per se, starting from the primary alcohols corresponding to the aldehydes. As moderate oxidation methods, the processes which do not cause any racemization of the centers of chirality in compounds of Formula VIII, for example oxidation with activated oxalyl chloride (= Swern oxidation) or oxidation with triacetyl oxy -pe ry odi nano (oxidation of Dess-Martin, see for example Martin et al, JACS 113 (1991) - 7.277-7.287). If the oxidation is carried out according to the Dess-Martin method indicated above, an amino-aldehyde of the Formula VIII can be prepared according to a process indicated in the preceding literature or according to a process analogous thereto. For example, a primary alcohol that comes into question as a precursor for an aldehyde of Formula VIII can be reacted in a dip or 1 ar-apotic solvent, for example in a halogenated lower alkane. such as dichloromethane, with a small excess of the triacetoxyperiodinan, for example in the molar ratio of from about 1.2: 1 to about 1.4: 1, based on the compound used of Formula VIII. The reaction can be carried out at temperatures between -20 ° C and room temperature, preferably at 0 ° C. The primary alcohols corresponding to the aldehydes of Formula VIII are known or can be prepared from known precursor compounds by methods known per se. For example, the primary alcohols can be prepared by known reduction methods, for example by reduction with complex hydrocarbon complexes of alkali metals such as lithium aluminum hydride, from the acid precursor amino-box compounds! 1 i co s free corresponding. Preferably, ammonium carbonylates which are present in pure form as regards isomers are suitable, for example in pure form for the enantiomers, such as the 20-ami no carbide. However, pure a-amino acids can be used for the non-natural, commercially available enantiomers, for example obtainable from ChiroTech, Cambridge, (catalog of the collection "). The ChiroChem®, series 1, FMOC unnatural amino acids for medicinal and combinatorial chemists ", SCRIP No. 2311 / 20.02.1998, page 15). For the preparation of compounds of Formula I, wherein n is = 1, can conveniently depart from pure ß-ami as to the isomers, known per se, for example from Nohira et al., Bulletin of the Chemical Society of Japan 43 (1970) pages 2.230 et seq. In addition, pure isomers which are not suitable for the isomers, suitable for the invention, can also be prepared from ammonia-free pure isomers, by homo 1 , for example by homologation according to Arndt-Eistert according to the methods of D. Seebach et al., Helvética Chimica Acta (= HCA) 79 (1996) 913-941; pages 2.043 and following, and Synlett (1997) pages 437 et seq. The chiral ß-amino acids in a, in which R 5 has a meaning other than hydrogen, can be obtained in a manner known per se, for example by asymmetric alkylation of oxa zo 1 and chiral dinones with c 1 or rome t 11 - amides according to the method of D. Seebach et al., Synlett (1997) pages 437 et seq., or also according to other methods, known per se.

In step b) of the process, two new stereogenic carbon atoms result in the vi or 1 -substitutions of Formula IX by the reaction between the chiral amino-1 of Formula VIII and the product. chiral intermediate, which has resulted from a 2- to 1-quot 1-its 1-oxime of the Formula II by rotonation and trimester 1 ac ion. These new stereogenic carbon atoms are the C-3 and C-4 atoms in compounds of Formula IX. The substituents R 4 in C-4 and OM 2 (OR 12) 3 in C-3 adopt, in the case of the formation of the vines 1-their 1-oximes of the Formula IX according to the process according to the invention, always with high selectivity, of at least 95%, an "anti" orientation between them. The absolute configurations in the centers of chirality C-3 and C-4 resulting from new, are controlled in this case during the reaction in each case by the absolute configuration in the sulfur atom in compounds of Formula II, in the sense of a regio- and diastéreo-controlled reaction. If the sulfur atom in compounds of Formula II possesses the R configuration, the prochiral carbonyl group in the aldehydes of Formula VIII is attacked from the S i side. If, on the contrary, "the sulfur atom in compounds of Formula II possesses configuration S, the prochiral carbonyl group in the aldehydes of Formula VIII is attacked from the R e side. By the absolute configuration of the compounds of the Formula IX, which has been established in this manner, also establishes as a "cis" orientation also the stereochemistry of the compounds of Formulas I in the corresponding centers of chirality The absolute co-configuration on the chiral carbon atom of an ami no - 1-Dehyde of Formula VIII has little influence on the stereochemistry at the carbon atoms C-3 and C-4 of the compounds of Formula IX The treatment of compounds of Formula IX with a base in step c) of The process, in order to produce compounds of Formula Xa, can be carried out in a manner known per se directly following step b) of the process, without the need for isolation of the compounds of the Formula IX The carrying out of the reaction can therefore be carried out in the solvents indicated above and at the temperatures indicated above, between -100 ° C and -50 ° C, preferably at -78 ° C. Suitable bases are the non-nucleophilic organic bases soluble in the reaction mixture, such as piperidine. Usually, the base is used in an amount greater than stoichiometric, for example in the molar ratio of about 5: 1 to about 15: 1, preferably about 10: 1, based on the amount of compounds of the Formula used IX, which have been formed from compounds of Formula II. After the addition of the base has been carried out, it can be thawed, first at 0 ° C and subsequently at room temperature, and the reaction mixture can be treated in a usual manner. By separating the amino protecting group R901 from compounds of Formula IX a ring-closing reaction is initiated to form compounds of Formula Xa. Especially for the compounds of Formula IX, in which R4 does not represent hydrogen, the cyclization reaction proceeds in such a way that the free radical radicals in the position 5 of the compound resulting from Formula Xa always adopt the "trans" arrangement relative to the hydroxyl group in the 3-position of the resulting cyclic network. If desired, the ring nitrogen atom of the resulting azacyclo can then be reacted further. in a manner known per se with a compound, which contains a group suitable for the reaction with a secondary amine. For example, a reaction of the nitrogen atom with carboxylic acids known per se for the formation of peptide bonds can be carried out. EquallyThe aforementioned carbon atom can also be alkylated in a manner known per se, for example by reaction with an alkyl halide such as a phenyl lower alkyl halide, for example benzyl chloride. In accordance with these methods described above or otherwise known per se, the nitrogen atom can also be blocked with a usual amino-protecting group, preferably with a stable protecting group against bases. As a protective group which is stable against bases, protective groups which form a carbamate, preferably the protective group tert-butyl-oxo-carbonyl (= BOC), are preferably used. Starting from compounds of the formula Xa, the optional protective groups can be separated again, if desired, also in a manner known per se, and optionally in a selective manner. Compounds of Formula Xa or compounds obtainable from compounds of Formula Xa by removal of protecting groups, are new compounds with useful properties, for example as intermediates for the preparation of compounds of Formula I. The (2S, 3R, 4R, 5R, S s) - 2 -benz 1 - 3 - hi dr ox i - 5 -. { N - [(S) -1-hydroxy-3-methyl-but-2-yl] -4-met11-phenyl-sulfonimido-yl-methyl} -4-methyl-l- (4-methyl-f-enyl-sulfonyl) pyrrolidine is already known from the publication on the Internet under the address "www.iucr.ac.uk" by M. Bolte, Acta C rysta 11 og r aph i ca Section C, electronically published article QA0019 [= (IQCr) Act C Paper QA0019]. In the indicated publication there is no mention of the preparation of this code. The cleavage by reduction of the sulfur bond to-1 to 1 in a compound obtained from Formula Xa or in a compound obtained from a compound of Formula Xa by the reactions described above in the ring-nitrogen atom, in step d) of the process for the preparation of compounds of Formula Ib can be carried out in a polar or weakly polar solvent previously indicated for the reaction of compounds of Formula III with compounds of Formula IV. Preferably, THF can be used. As reagents for the cleavage of the bond to z or f to which, for example, reducing agents such as Raney nickel, lithium naphthalenide or samarium iodide (II) are suitable. Preferably, samarium iodide (II) can be used. If samarium iodide (II) is used, this compound can be produced in a manner known per se i n s i t u from samarium and diiodo methane. Usually the samarium iodide (II) is used in an amount greater than stoichiometric, for example in a molar ratio of from approximately 3: 1 to approximately 7: 1, based on the compound used of Formula Xa. The cleavage of the sulfur bond - at 1 qu or 1 under the conditions of a base-induced reduction by reduction in a compound obtained from Formula Xa, in which R101 does not mean hydrogen, or in a compound obtained from a compound of the Formula Xa by the reactions on the ring nitrogen atom, described above, in the process step da) for the preparation of compounds of the Formula I, can be carried out in a polar or weakly polar solvent above indicated for the reaction of compounds of Formula III with compounds of Formula IV, or also within a partially halogenated lower alkyl compound, such as diolorothiamine. Preferably, dichloromethane can be used. As bases for the cleavage of the sugar bond to 1 by elimination in ß, non-nucleophilic organic bases such as bicyclic amidines are suitable, for example on 1-5 day z abi cycle [4.3.0] - 5 -nonne (= DBN) or the 1,8-diasa-bike cl or - [5.4.0] - 7 - unde ceno (= DBU). Preferably, the DBU can be used. Conveniently, the reaction is carried out by reacting the compound of the Formula Xa, indicated above, at temperatures between -25 ° C and -15 ° C, with a compound suitable for the formation of a good labile group in common with an oxygen atom. -geno from an aliphatic radical, or with a tet alkyl-lower alkyl-oxonium afluoroborate or such as triethyl-oxonium tetrafluoroborate known as "Meerwein salt". Preferably, methyl triflate can be used. Usually, the mixture resulting from the reaction, after the reaction has been carried out, is allowed to thaw to room temperature and then the aforementioned base is added. In the obtained compounds of Formula la, the relative orientation of the substituent s or p onimidoi 1 or in position 5, which has resulted in step c) of the process by ring closure to form compounds of formula Xa, and of the hydroxyl group in position 3 it is established as a relatively "trans" orientation between them. The compounds of Formula I, in which the substituent YH in position 3 can mean hydroxy or amino and / or in which the substituents YH in position 3 and R1-CHR2- in position 5 can also be located in "cis" orientation among them, it is possible to obtain, if desired, compounds of the formula by means of a nucleophilic substitution reaction at the ring carbon atom in position 3, which takes place by means of inversion, which is performed once or multiple voices.

Such nucleophilic substitution reactions are known per se, and can be carried out for example under the conditions of a Mitsunobu reaction. (see, for example Mitsunobu, Synthesis 1_ (1981) - 1-28). If for example compounds of the formula I are desired, in which YH represents hydroxy and in which the substituents OH in position 3 and R ^ CHR2- in position 5 are located in a "cis" orientation between them, it can be carried out ^ suitably a Mitsunobu reaction, adding a solution of a compound of Formula la, in which the additional hydroxyl groups, if any present, are blocked by protective groups, and of triphenylphosphine, in an inert organic solvent under the conditions of the reaction, such as a cyclic or open-chain (alkyl lower) ether, for example diethyl ether or THF, at a pre-charge of a solution of diethyl azo-dicarboxylate (= DEAD) and an acid , for example phosphoric acid or a carboxylic acid such as benzoic acid. The reaction can be carried out preferably at room temperature. The ester of a desired compound of formula I, obtained in this way, can, if desired, then be further cleaved in a manner known per se, in order to obtain the free hydroxyl group in the 3-position. example compounds of Formula I, in which Y represents NH and in which the amino substituent in position 3 and the substituent R1-CHR2- in position 5 are located in "cis" orientation between them, a reaction of Mitsunobu by adding a DEAD solution in one of the aforementioned solvents to a pre-charge of a triphenylphosphine solution, of a compound of Formula la, in which the other hydroxyl groups if any present are blocked by protective groups, and an appropriate reagent for the nucleophilic substitution of a hydroxyl group for an amino group in aliphatic radicals, such as phthalimide. The resulting intermediate product, for example an N-substituted phthalimide, can then be treated in a protic solvent such as a lower alkanol, for example ethanol, with a reagent suitable for the release of the amine of Formula I, such as hydrazine. If for example compounds of the formula I are desired, in which Y represents NH and in which the substituents YH in position 3 and R1-CHR2- in position 5 are located in "trans" orientation between them, in a It is possible, first of all, to carry out an inversion, as described above, of the ring carbon atom in position 3, with obtaining the hydroxy substituent, and in this intermediate product of Formula I it is then possible to carry out a previously described substitution of the hydroxyl group for an amino group with renewed reversal of the ring carbon atom in position 3. The compounds obtained of the formula I can be isolated from the reaction mixture of a way known. The optional protective groups can be separated again if desired in a known manner, optionally selectively, and the YH group can be blocked if desired with known protective groups. The NH group optionally released at position 1 of the cyclic basic framework can be reacted, if desired, with the reagents mentioned above, capable of N-alkylation or amide formation, or can be blocked with a group amino protector. If desired, the compounds of the formula I, which contain reactive amino groups, can be converted in a manner known per se into acid addition salts. Examples of suitable acids are, for example, mineral acids, such as hydrochloric acid or sulfuric acid, or organic acids such as sulphonic acids, for example me t i 1-s or 1-ionic acid or p-toluene-5-phonic acid., or carboxylic acids, such as acetic acid, tartaric acid, tartaric acid or citric acid. The compounds of the general formulas I, in which R8 has the above-mentioned meaning except for esterified methyl, benzyl and carboxy, are novel compounds and constitute valuable starting substances, for example for the preparation of chiral catalysts for asymmetric synthesis , for the preparation of biologically active alkaloids or porphyrins, as well as for the preparation of pharmacologically interesting compounds. The following Examples should explain the invention in greater detail, without limiting its extension. The numbering of the ring atoms in the compounds of the Examples, especially the "chiral carbon atoms", refers to the numbering of the ring atoms indicated in General Formula I.

Example 1 (+) - (2S, 3S, 4S, 5S) -2-Isobu-3-hydroxy-4,5-dimethyl-N- (tert -buoxycarbonyl) -pyrrolidine A) 6.0 g " of the S-2-ami non-4-methyl-1-p in tannol 1 protected by ammonium by FMOC (obtained by reduction of leucine with lithium aluminum hydride) were suspended under a nitrogen atmosphere and to the exclusion of 100% water. ml of dichloromethane and cooled to 0 ° C. To this preload was added in one portion 10.0 g of 1,1-triacetoxy-1,1-dihydro-1,2-benzo-yodoxol-3. (H H) -one (= peryodynan) as a solid material and the resulting reaction mixture was stirred for two hours at room temperature, then the reaction mixture was poured into a solution, covered with 100 ml of ether, The base was 130 ml of a 10% aqueous solution of sodium thiosulfate and 360 ml of a saturated aqueous solution of sodium hydroxide was added, and the aqueous phase was extracted once with 100 ml of ether. organic The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was concentrated by evaporation under reduced pressure and S-2-amino-4-methyl-1-val to the crude FMOC-protected dehydrate obtained in this manner was used without further purification for the next reaction. In order to determine the optical purity, a part of the obtained aldehyde was isolated by crystallization from a mixture of ether and hexane. The excess between enantiomers was determined by NMR spectroscopy (nuclear magnetic resonance) with the addition of the chiral shift (tris) reagent (3 - (hep taf 1 uo ro -pr op i 1 -hidr o ti len) -d- canf or ato] -pr as eodimi or (III) [= Pr (hfc) 3]. By integration of the signals, separated at the baseline, from the aldehyde protons, the excess between enantiomers (ee) could be determined as 95%. B) 1.82 g of magnesium chips were covered with approtely 10 ml of diethyl ether and activated by the addition of 500 mg of freshly distilled crotyl bromide. To this preload was slowly added dropwise a solution of 10.0 g of crotyl bromide (= c i s / t r an s - 1 -b romo-2-butene) in. 100 ml of diethyl ether at 0 ° C, under protection with argon and excluding moisture. The resulting mixture, after the addition was made, was heated to boiling for 30 minutes. The resulting ethereal solution of c r o t -magne s i o bromide was separated from the unreacted magnesium and reacted directly in solution without further treatment. To determine the content of the Grignard solution previously prepared, a solution of 180 mg of (-) - menthol and a pinch of phenanthroline in 3.0 ml of THF at 0 ° C was cooled. The addition of the Grignard solution to this preload was evaluated until the color turned red and the necessary amount of Grignard solution was determined by differential weighing for the next reaction. _ From the quotient between the heavy and introduced amount of menthol in mmol, and the mass of the Grignard solution that is necessary for the titration. until the color is changed, in g, the content of the Grignard solution, expressed in mmol / g, is established. C) To a solution, cooled to -40 ° C, of 2.3 g of (+) - (S s) - 4 (R) - is op r op i 1 - 2 -p - to 1 i 1 - 4 5-Dihydro [1, 2 → 6, 3] oxat iazo 1 - 2 - or xi do in 40 ml of THF, was added dropwise, under argon protection and to the exclusion of moisture, 46 g of the solution previously obtained from croti-1 -magne-bromide, dissolved in 100 ml of diethyl ether. After the addition was complete, stirring was continued for five minutes at the indicated temperature, before the reaction mixture was allowed to warm to 0 ° C. It was stirred for another 45 minutes at this temperature and then 50 ml of a saturated aqueous solution of ammonium chloride was added thereto. The organic phase was separatedThe aqueous phase was extracted twice with ether and the combined organic phases were dried over sodium sulfate. magnesium. The solvent was then concentrated by evaporation under reduced pressure and the residue chromatographed on silica gel (eluent: initially a mixture of acetic acid ethyl ester and n-hexane 1: 3 v / v, the composition of which was continuously modified until get to the 3: 1). 1.4 g of (Rs, 1 R) - N - [1- (hydroxymethyl) -2-methyl-propyl] -S- (2-butenyl) -p -t-ol-uene-s were obtained. as a colorless oil, IR (film) = 3440, 1220, 1115 cm "1, optical rotary power [= + 3, 3, 0.5 in dichloromethane) D) -A solution, cooled at 0 ° C, of 1.4 g of the sulfoximide above obtained and 0.7 ml of ethylidene 1-amine in 13 ml of dichloromethane, 0.6 ml of chlorine-triethyl ether were added dropwise, under argon protection and to the exclusion of moisture. 1 - if 1 year After the addition was completed, stirring was continued for 15 minutes at 0 ° C. It was then allowed to thaw to room temperature and the reaction mixture, after the reaction had been completed, was poured 25 g of ice were added to a mixture of 25 ml of ether, the aqueous phase was extracted 3 times, each time with 10 ml of ether, the organic phases were combined and dried over magnesium sulfate.The solvent was concentrated by low evaporation. reduced pressure and the remaining residue was purified by chromatography on silica gel (eluent: ether mixture and n-hexane 1: 1 v / v) 1.75 g of (+) - (Rs, 1 R) -N- [1 - (tr ime ti 1 - si li 1 ox i -me ti 1 -propyl) -2-methyl] -S- (2-butenyl) -p-toluene-sulfoximide as a colorless oil, IR (film) = 1240, 1080, 840 cm "" 1, optical rotary power [oc] D20 = + 15.5 ° (c = 1.0 in dichloromethane). E) A solution of 1.47 g of the 2-alkenyl sulphoximide protected by TMS, previously obtained, in 8 ml of toluene was cooled to -78 ° C, and under protection by argon and with exclusion of moisture was mixed with 2.75 ml of a 1.6 molar solution of n-but i 1-lithium in n-hexane. The reaction mixture was allowed to stir at the indicated temperature for 15 minutes and then 4.8 ml of a 1-molar solution of chloro-t r is (i s opropax i) t i t ani in n-hexane was added. It was stirred for another 5 minutes at -78 ° C, thawed at 0 ° C and stirred at 0 ° C for 30 minutes. Then, the reaction mixture was again cooled to -78 ° C. To this preload was added a solution of 2.8 g of the amine-aldehyde obtained above in section A) in 8 ml of THF. The mixture was allowed to continue stirring for 60 minutes at -78 ° C, 4 ml of piperidine were added thereto and it was allowed to warm to 0 ° C. After 10 minutes, the reaction mixture was poured into 120 ml of a saturated, intensely stirred ammonium carbonate solution, covered with 12 ml of ethyl acetate (= EA). This mixture was allowed to stir for 30 minutes and then the phases were separated. The organic phase was washed with 40 ml of a saturated solution of ammonium chloride and the combined aqueous phases were extracted three times with EA. The combined organic phases were dried over magnesium sulfate and the solvent was concentrated by evaporation under reduced pressure. The remaining residue was taken up with a suspension of 0.6 g of potassium carbonate in 10 ml of methanol and stirring was continued for 60 minutes. Then undissolved potassium carbonate was filtered off and the filtrate was cold at 4 ° C. The precipitated solid was separated by filtration, washed with a small amount of cold methanol at 4 ° C. and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was taken up in 5 ml of toluene and filtered on silica gel (eluent, initially a mixture of ether and hexane 1: 3 v / v and then EA). The polar fraction, which contained pyrrolidine, was concentrated and taken up in 4 ml of dioxane. To this preload, 1.0 g of di-tert-bu ti 1 or [= (BOC) 20] di-carbonate and a solution of 0.7 g of sodium hydrocarbon in 8% were added. ml of water. The mixture was allowed to stir for 10 hours, the solvent was concentrated by evaporation under reduced pressure and the remaining residue was partitioned between 5 ml of water and 10 ml of ether. The aqueous phase was extracted three times with ether and the combined organic phases were dried over magnesium sulfate. After renewed concentration by evaporation of the solvent under reduced pressure, the residue obtained was purified by chromatography on silica gel (eluent: ether / hexane mixture 3: 1 and / v). 1.0 g of (RS, 1'R, 2S, 3S, 4S, 5R) -N '- [(1-hydroxymethyl) -2- (methyl-propyl)] -S-4-hydroxy-3- was obtained methyl-2- (4-methyl-phenyl-sulfo-nimidoyl-methyl) -5-isobutyl-N-tert-butoxy-carbonyl) -pyrrolidine as a colorless foam, optical rotary power [a] 2o -4 ° C c 0 , 1 in dichloromethane), IR (film) = 3419, 1674, 1256, 1097 cm "1. F) To a suspension cooled to 0 ° C of 1.67 g of samarium in 40 ml of THF was added dropwise In total, 2.4 g of di-odo-methane were added, after the addition had been carried out, it was stirred at 0 ° C for 15 minutes, before the reaction mixture was thawed at room temperature. room temperature for a further 60 minutes and then a solution of 1.0 g of the above-obtained 2-yl-1-methyl compound obtained in a mixture of 1.2 ml of methanol and 2.5 ml was added. of THF The reaction mixture was stirred for 4 hours and then mixed with 110 ml of an aqueous solution saturated with ammonium chloride. After the first phase separation, the aqueous phase was mixed dropwise with a 0.5 N aqueous solution of hydrochloric acid, until the phase was clarified. The aqueous phase was extracted three times with ether. The combined organic phases were dried over magnesium sulfate and the solvent was concentrated by evaporation under reduced pressure. Chromatography of the remaining residue on silica gel (eluent: ether: 3: 1 v / v mixture of ether and n-hexane) gave 0.5 g of the title compound as a colorless solid, m.p. = 97 ° C, optical rotary power [OC] D2 ° = + 66 ° (c = 1.0 in dichloromethane).

Example 2 (+) - (2S, 3S, 4S, 5R) -3-hydroxy-5-methyl-2-phenyl- (1-aza-N- (er-bu oxycarbonyl)) -bicyclo (3.3.0 ] Oc cess A) To a solution cooled to -78 ° C 3.98 g of (+) - S s - 4 R- is op r op i 1 - 2 - p-to 1 i 1 - 4, 5 -dihi dr or [1, 2? 6, 3] oxa thiazo 1 -2 - ox in 40 ml of THF, 16.6 ml of a 1.6 molar solution of methyl lithium in hexane were added dropwise under argon protection and exclusion of moisture. After the addition was complete, stirring was continued for five minutes at the indicated temperature, before the reaction mixture was allowed to warm to 0 ° C. It was stirred for another 45 minutes at this temperature and then 160 ml of ammonium chloride was added. After separation of the organic phase, the aqueous phase was extracted twice more with 20 ml of ether and the combined organic phases were dried over sodium sulfate. The solvent was then concentrated by evaporation under red pressure. The remaining residue was dissolved at room temperature in 80 ml of dichloromethane and thereto was added 3.8 g of tert-bu ti chloride 1-dime ti 1-si1 i1, 0.6 g of N, N d 1-amino-pyridine and 2.4 g of ethyl-dimethyl-1-amine were added and the mixture was stirred for 18 hours. The mixture was then poured into 40 ml of a mixture of ice and water, the organic phase was separated and the aqueous phase was extracted three times, each time with 20 ml of dichloromethane. After the combined organic phases had been dried over sodium sulfate, the solvent was concentrated by evaporation under red pressure. Purification of the residue on silica gel (eluent: ether / n-hexane = 1: 1 v / v mixture) gave 6.0 g of (-) - R3 - N (1 R) - N - '[1 - ((tert-Butyl-dimethylsilyl) oxy) methyl-2-methyl-propyl] -S-methyl-1-S- (4-methyl) 1 -f or 1) is as a colorless oil , optical rotary power [-] D "° = -43.2 ° (c = 0.8 in dichloromethane); IR (film) = 1230, 1130 B) To a solution, cooled to -78 ° C, of 6.5 g of the previously obtained methyl ester, 45 ml of toluene were added dropwise, under argon protection and exclusion of moisture, 12.45 ml of a 1.6 molar solution of n-butyl lithium in n-hexane. It was stirred for 15 minutes at the indicated temperature and then 2.2 g of cyclopep in anonone were added dropwise thereto without dilution. After 10 minutes the reaction mixture was allowed to warm to room temperature. It was stirred for another 30 minutes at this temperature, before the batch was cooled to -78 ° C and 9.2 g of trif 1 or one of the tributylum was added dropwise. 1 - yes 1 i lo. After five minutes it was warmed to room temperature and stirred for another three hours. After it had cooled rapidly to -78 ° C, 24.9 ml of a 1.6 molar solution of n -b u t i 1-1 i t in n-hexane was added dropwise. After stirring for 3 minutes at the indicated temperature, it was left to thaw at room temperature and stirring was continued for 18 hours. The reaction mixture was poured into 160 ml of a saturated aqueous solution of ammonium chloride, extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was concentrated by evaporation under red pressure and the remaining residue was purified on silica gel (eluent: ether / n-hexane mixture 1: 6 v / v). 5.5 g of (-) - Rs- (1 R) -N - [1 - ((tert -buti-1-dimethyl-silyl) oxy) ethyl-2-ethyl-propyl] -S-cyclopent-1 were obtained -in-l-yl-methyl) -S- (4-methyl-phenyl) -sulfoximide as a colorless oil, optical rotary power [-] D20 = -2.5 (c = 1.6 in dichloromethane), IR ( film) = 1240, 1120 cm-1. C) In the manner described above in section 1E), a solution of 2.95 g of the c i c 1 op in t e n i 1 - s or 1 or more preferably obtained in 21 ml of toluene was reacted with 4 ml of toluene., 8 ml of a 1.6 molar solution of n-bu ti 1 - 1 itio in n-hexane, 8.3 ml of a 1 molar solution of chloro-tris (is op ropax i) - ti tani or in n- hexane, a solution of 5.0 g of S-α-amino-f in i-eta n-1 protected by FMOC in _40 ml of TLHF and 7 ml of piperidine. Chromatography on silica gel (eluent: a mixture of ether and n-hexane = 1: 3 v / v) afforded 3.9 g of (2S, 3S, 4S, 5R) -Rs -N ( 1 R) -N - [1 - ((tert -bu thi 1 -dimethyl-silyl) oxy) methyl-2-methyl-propyl] -3-hydroxy-2-phenyl-5- (p-tolyl-sulfonimidoyl-methyl) -2-aza-bicyclo- [3.3.0] oct ano.Optional rotary power [-] D20 = + 2.8 °, (c = 0.6 in dichloromethane); IR (film) = 3443, 1251, 1103, 835 cm "1 D) To a solution of 3.9 g of the above-mentioned bicyclic compound obtained in 20 ml of dichloromethane and 40 ml of water were added 0.45 g of water. Sodium bromoate and 3.0 g of di-tert-butyl dicarbonate were stirred for 12 hours After the solvent had been concentrated by evaporation under reduced pressure, the residue obtained was partitioned between 5 ml of water and 10 ml of ether The organic phase was separated and the aqueous phase was extracted twice with ether, drying of the combined organic phases over sodium sulphate, concentration by evaporation of the solvent under reduced pressure and chromatography of the residue remaining in the solvent. silica gel (eluent: ether / n-hexane = 1: 1 v / v mixture) gave 4.39 g of (-) - (2S, 3S, 4S, 5S) -Rs-N (lR) -N - [l- ((tert-Butyl-dimethyl-silyl) oxy) methyl-2-methyl-propyl] -3-hydroxy-2-phenyl-5- (p-tolyl-sulfonimidoyl-methyl-2-aza- (N -ter-butoxy-carbonyl) -bicyclo [3.3.0] octane, optical rotary power [a] D20 = -6.2 ° (c = 0.9 in dichloromethane); IR (film) = 3473, 1682, 1253, 837 cm "1. E) A solution cooled to 0 ° C of 0.42 g of the protected bicyclic compound in nitrogen, which has been obtained above, in 6 ml of THF , mix it with 0.25 g of tetrabutyl ammonium fluoride, after 15 minutes it was warmed to room temperature and then stirred for another 12 hours.The reaction mixture was poured into 10 ml of water, which had been covered with 5 ml of ether After the organic phase had been separated, the aqueous phase was extracted three times with ether, the combined organic phases were dried over sodium sulphate and the solvent was concentrated by evaporation under reduced pressure. silica (eluent: mixture of ethyl acetate and n-hexane = 1: 1 v / v) yielded 0.35 g of (-) - (2S, 3S, 4S, 5S) -Rs-N (IR) - N- [1- (hydroxymethyl) -2-methyl-propyl] -3-hydroxy-2-phenyl-5- (p -tolyl-sulfonimidoyl-methyl-2-aza- (N-tert-butoxycarbonyl) - bicyclo- [3.3.0] octane. [] 20 -14 , 1 c 2, 7 e n dichloromethane); IR (film) = 3473, 1681, 1252 ci "1. F) To a suspension cooled to 0 ° C of 0.56 g of samarium in 13 ml of THF was added dropwise in total 0.84 g of di. iodine-not, after the addition was made, it was stirred for 15 minutes at the indicated temperature, before the reaction mixture was thawed at room temperature, allowed to stir for another 60 minutes and then a solution was added. of 0.28 g of the compound of 5-s or fonimido i 1 or previously obtained, in a mixture of 1 ml of methanol and 2 ml of THF The reaction mixture was stirred for four hours and then poured into 110 ml of water. a saturated solution of ammonium chloride After the organic phase had been separated, a 0.5 N solution of hydrochloric acid was added to the aqueous phase until the suspension had been clarified.The clear aqueous phase was extracted twice with ether The combined organic phases were dried over sodium sulphate. sodium and the solvent was concentrated by evaporation under reduced pressure. Chromatography of the remaining residue in silica gel (eluent: ether / n-hexane = 1: 4 v / v mixture) gave 0.11 g of the title compound as a colorless solid, m.p. = 176, 8 ° C, [a] D 20 + 50.7 ° (c = 0.56 in dichloromethane); IR (film 3439, 1661 cm "1.

Example 3 (+) - (2S, 3R, 4R, 5S) -3-hydroxy-S-methyl-2-phenyl- (1-aza-N-ter-b-toxy-carboni 1) -bicyclo [3.3. 0] octane Analogously to the preparation requirement of Example 2, the title compound was obtained as an oil from the corresponding educts. [-] 20 = + 34, 5 ° C. Example 4 (-) - (2S, 3R, 4R, 5S) -3-Hydroxy-5-methyl-2-phenyl-1-aza-bicyclo- [3.3. O] Octane 205 mg of (+) - (2 S, 3 R, 4 R, 5 S) - 3 - hi dr ox i -5-methyl-2-phenyl- (1-aza-N-tert-butoxy) carbonil) -bi ci c 1 or [3.3.0] oct anus were dissolved, under an atmosphere of argon and excluding moisture, in a mixture consisting of 1.6-1 ml of a 4.0 M solution. c 1 gold - tr ime ti 1 - si 1 a not in dichloromethane and 4.84 ml of a solution of 4.0 M phenol in dichloromethane, and stirred for 20 minutes at room temperature. It was then poured into 10 ml of a 10% aqueous solution of sodium hydroxide solution, the organic phase was separated, the aqueous phase was further extracted twice, each time with 5 ml of dichloromethane and once with 5 ml of ether. The combined organic phases were dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was poured onto silica gel (eluent: a mixture of ethyl acetate and n-hexane 10: 1 v / v). 113 mg of the title crystalline compound, m.p. = 84.5 ° C, optical rotary power [oc] D 20 46.4 1.0 in di c lor ome t an).

Example 5 (+) - (2S, 3S, 4R, 5S) -3-Ami-no-5-methyl-2-phenyl- (1-aza-N-tert-butoxy-carbonyl) -bicyclo [3.3. 0] octane A) To a solution of 200 mg of (-) - (2S, 3R, 4R, 5S) -3-hydroxy-5-methyl-2-f-enyl-1-aza-bi-cy 1 or [3.3. 0] O in 1.5 ml of THF were poured at room temperature, under an argon atmosphere and excluding moisture, 241 mg of triphenylphosphine and 135 mg of phthalimide. Then 0.14 ml of DEAD was added over the course of 2 min. After a reaction time of 10 hours, the solvent was concentrated by evaporation under reduced pressure and the residue was taken up in 5 ml of ether. After having separated by filtration with respect to the undissolved residue and having evaporated the solvent under reduced pressure, (2S, 3S, 4R, 5S) -5-methyl-2-phenyl-3 was obtained. -phthalimido-l-aza-bicyclo [3.3.0] octane as a crude product, which was used without further purification for the subsequent reaction.

B) 174 mg of the crude product obtained above were dissolved in 3 ml of dioxane. To this preload 220 mg of di-1-butene dicarbonate and 63 mg of sodium hydrogencarbonate as well as 0/5 ml of water were added thereto, and the resulting mixture was stirred for 1 hr. 16 hours at room temperature. The solvent was concentrated by evaporation under reduced pressure and the remaining residue was taken up in water and ether. The phases were separated and the aqueous phase was extracted 2 times, each time with 5 ml of ether. The combined organic phases were dried over magnesium sulfate, before the solvent was concentrated by evaporation under reduced pressure. Chromatography of the remaining residue on silica gel (eluent: a mixture of ether and n-hexane 1: 3 v / v) gave 115 mg of (2 S, 3 S, 4 R, 5 S) -5-me 1 - 2 - fei 1 - 3 - ft to imi do -1- (aza-N-tert-butoxy-carbonyl) -bicyclo [3.3.0] oily octane. C) A solution of 115 mg of the phthalimido-b icic 1 or [3.3.0] octa not previously obtained, in 2 ml of ethanol, was mixed with 400 mg of hydrazine hydrate (24%) and the resulting mixture was heated at reflux for 8 hours.

The solvent was concentrated by evaporation under reduced pressure, the remaining residue was taken up in 10 ml of ether and the organic phase was extracted with 10 ml of a 10% aqueous sodium hydroxide solution. The aqueous phase was extracted 2 times, each time with 10 ml of ether and the combined organic phases were dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure and 74 mg of the title crystalline compound were obtained, p.f. = 92.1 ° C [a] D20 = + 24.1 ° (c = 1.0 in dichloromethane). According to the methods indicated above, it was also possible to prepare the compounds of the formula indicated in the following Table. The following abbreviations are used in the Table: i-Bu = isobutyl Bn = benzyl BOC = ter -bu t yl -oxi-ca rboni lo TBOM = ter -but i 1 -oxime ti 1 or Ph = phenyl Desc. = Decomposition at heat NN = record not occupied (Ti co

Claims

1. Procedure for the controlled preparation of the ochemistry of compounds of the General Formula I, wherein the group R1R'CH at the 5-position of the cyclic basic unit and the hydroxy group at the 3-position of the cyclic basic unit is each other in the trans position and in which the substituent EL4 at position 4 of the The hydroxy group in the 3-position of the basic cyclic group is each with respect to the other in the cis position and in which n means 0 or 1, R1 means hydrogen, C?-C6 alkyl, or phenyl-Ci-Cß alkyl optionally substituted once or "multiple times in the phenyl ring with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy, and -R 2 signifies hydrogen, or R 1 and R 2 together mean a double-bonded methylene group, which may be to be substituted with C1-C5 alkyl, or with phenyl-C1-C5 alkyl and substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy; R means hydrogen, and R 4 signifies hydrogen, lower alkyl, or phenyl-lower alkyl optionally substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or hai o-lower alkoxy, or R 3 and R4 also mean in common a C2 alkylene chain or a C3-C3 alkylene chain which, in the end, contains from 1 to 3 double bonds, which may be bridged by a C1-C2 alkylene optionally substituted once or twice with lower alkyl, R5 signifies hydrogen, lower alkyl, hydroxy, lower alkoxy, fe-lower alkyl or phenyl-lower alkoxy optionally substituted once or multiple times in the phenyl ring with lower alkyl, halo-lower alkyl, lower alkoxy or halo lower alkoxy / or lower alkyl phenyl or substituted lower alkoxy phenyl, R means hydrogen, and R7 signifies hydrogen, and R8 signifies hydrogen, cyano, carboxy optionally this is, c arboni 1-ami not optionally substituted once or twice in the nitrogen, a ring system, monocyclic or bicyclic, with 3 to 10 ring carbon atoms, optionally unsaturated once or multiple times, whose ring carbon atoms may be be replaced once or multiple times by nitrogen, oxygen and / or sulfur, and whose ring system may be substituted once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, halogen or with an alkylene chain lower, which is attached to two oxygen atoms bonded to adjacent carbon atoms of the ring system, or can also represent straight or branched C? -C? 2 alkyl, optionally containing one or more double bonds, which may be substituted once or multiple times with halogen, hydroxy, lower alkoxy, optionally esterified carboxy, cyano, mercapto, lower alkylthio, amino, lower alkylamino, carb on i 1-ami n or optionally substituted once or twice in the nitrogen, a ring system, monocyclic or bicyclic, with 3 to 10 ring carbon atoms, optionally unsaturated once or multiple times, whose ring carbon atoms may be replaced once or multiple times by nitrogen, oxygen and / or sulfur, and whose ring system may be substituted once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, halogen, or with a lower alkylene chain, which is attached to two oxygen atoms bonded to adjacent carbon atoms of the ring system, or R5 and R8 can also form, in common with the carbon atoms, to which they are attached, a ring system, monocyclic- or bicyclic , with 5 to 10 ring carbon atoms, which optionally contains 1 to 3 double bonds, whose carbon atoms not bearing the R5 or R substituents may be replaced once or multiple times by sulfur and, oxygen and / or nitrogen, and which may optionally be substituted once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, hydroxy, halogen or with a lower alkylene chain, which is attached to two oxygen atoms bound to contiguous carbon atoms of the ring system, or R6 and R7 can also form a bond together and R5 and R8 can form in common with the carbon atoms, to which they are attached, a ring system ? aromatic, which can be condensed - with another 2 to 4 carbon atoms to form a bicyclic ring system, which in total contains 8 to 10 ring carbon atoms, which has a total of 3 to 5 double bonds, carbon atoms that do not carry the substituents R5 and R9 of this ring system from C? to C? 0 are replaced once or multiple times by sulfur, oxygen and / or nitrogen, and this C ring system can be It must be substituted once and again with lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, hydroxy, halogen, or with a lower alkylene chain which is attached to two oxygen atoms bound together. to contiguous carbon atoms of the ring system, R means hydrogen, lower alkyl, phenyl-lower alkyl optionally substituted on the phenyl ring once or multiple times with lower alkyl, halo-lower alkyl, lower alkoxy or halo-lower alkoxy ior, or means an amino protecting group, or R8 and R can also form in common a C3-C4 alkylene chain, and their salts by addition of acids, reactive groups can, and are present in compounds of the Formula I, be blocked by appropriate protecting groups, characterized in that a) for the preparation of a compound of general Formula II, in which R3 and R4 have the meanings above, R101 has the meaning indicated above for R1 with the exception of an optionally substituted methylene group, Ar represents phenyl optionally substituted once or multiple times with lower alkyl, RIO means lower alkyl, or phenyl optionally substituted on the phenyl ring once with lower alkyl or with hydroxy, which is protected by an appropriate proteg group, or means phenyl-lower alkyl optionally substituted on the phenyl ring once with lower alkyl, and Rllel represents a silyl proteg group, is reacted consecutively with an appropriate base for its deprotonation, with an organometallic reagent of the general Formula VII, XM '(OR 12) 3 VII wherein X represents halogen, M means a quadrivalent transition metal and R 12 represents lower alkyl, phenyl or phenyl-lower alkyl, and a stereoisomer of a compound of the general Formula VIII, wherein R5, R6, R7 and n possess the previous meanings, R801 has the meaning of R8, with any reae groups, if necessary, blocked by eatable proteg groups against bases, R901 represents hydrogen or, in common with R801, a C3-C4 alkylene chain, and R13 means an unstable proteg group against bases, to form a stereoisomer of a compound of the general Formula, IX, wherein R101, R3, R4, R5, R6, R7, R801, R901 R or Ruoi; R 2 2 Ri 3 ^ n ^ Ar and M 2 possess the above meanings, b) the compound obtained from Formula IX is transformed, by treatment with an appropriate base for the elimination of the group R, into a compound of general Formula Xa, For wherein R101 R ', 801, 901 R, 10, n and Ar have the above meanings, and Rll is for hydrogen or a silyl proteg group and as long as R901 represents hydrogen, the nitrogen atom in the fundamental set of the compound of formula Xa is blocked with a stable base proten group and a silyl proteg group is dissociated which if it still exists, and c) for the preparation of a compound of the general formula the link R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8 0 1 and n possess the above meanings and R, 902 represents a stable proteg group against bases or, in common with R801, a C3-C4 alkylene chain, ca) a compound obtained from Formula Xa is reacted with an appropriate reagent for cleavage by redun of the sulfur-alkyl bond, to obtain a compound of the general Formula Ib, wherein R101, R3, R4, R5, R6, R7, R801, R902 and n have the above meanings or cb) in a compound obtained from Formula Xa, in which R101 does not represent hydrogen, the bond is broken down - at 1 to 1 or after electrophilic aation of the unit of its 1 fon imido i 1, under the conditions of a base induced elimination, to obtain a compound of the general Formula I, wherein R3, R4, R5, R6, R7, R801, R902 and n have the above meanings and R102 represents C3-C5 alkyl, or phenyl-lower alkyl optionally substituted once or multiple times on the phenyl ring with lower alkyl , halo-lower alkyl, lower alkoxy or halo-lower alkoxy, whose lower alkylene chain can contain from 1 to 5 carbon atoms, and a compound obtained from the Formula is reacted as desired once or multiple times by conversion chemistry, in each case mediating inversion of the configuration at the ring carbon atom at position 3 of the compounds of Formula la, with a nucleophilic reagent suitable for the renewed generation of an OH group or for the generation of a group NH2 in position 3, and / or, if desired, the possible protee groups existing in compounds of the formula are separated again, and if desired, the NH group has not yet been released, in position 1 The cyclic fundamental network is reacted with a reae agent capable of N-alkylation or with a reagent capable of forming amides, or is blocked with an amino protecting group, and / or compounds of the Formula Ia, or compounds obtained from these compounds by the nucleophilic substitution reactions indicated above, which take place under inversion, are made to react if desired to form salts by addition of acids, in order to obtain compounds of Formula I.

2. Process according to claim 1, for the preparation of compounds of the general formula Ib and optionally the NH group released in the position 1 of the set or cyclic fundamental structure with a reactant capable of N-alkylation or a formation of amide or blockage of the optionally released NH group, mentioned compounds obtainable with an amino protecting group, according to Claim 1.

3. Procedure of. according to claim 1, characterized in that as an amino protecting group R13 in compounds of formula VIII an unstable protection group is used in base and in process step b) as a reactant for the removal of protection group R 13 is used one base.

4. Process according to claim 3, characterized in that the base unstable protection group is the fluoren-9-yl-methyloxycarbonyl group.

5. Process according to claim 4, characterized in that piperidine is used as the base.

6. . Process according to the rei indication 1, characterized in that at least the procedure step a) is using toluene as a solvent.

7. Process according to claim 1, characterized in that in process step ca) it is used as a reactant for the reductive dissociation of the bond s or p-1-alkyl in compounds of the general formula Xa iodide II of samarium.

8. Procedure according to the rei indication 1, characterized in that in the compounds of the general formulas the ', the, Ib, le, II. IX and Xa each time R4 does not mean hydrogen.

9. Process according to claim 1, characterized in that it is used as a protection group of silyl R 1101 ter-b u t i 1 dime t i 1 s i 1 i 1 o o t r ime t i 1 s i 1 i 1 o.

10. Process according to claim 1 for preparing compounds of the general formula la1, characterized in that, R8 means hydrogen, lower alkyl, phenyl, lower alkyl phenyl, or lower alkyl lower alkoxy, or R6 and R7 with which they form a bond and R5 and R8 together with the carbon atoms to which they are attached, form an aromatic ring system with 6 carbon atoms or wherein R 8 together with R 9 form an alkylene chain with 3 to 4 carbon atoms.

11. Compounds of the general formula Xa according to claim 1, as well as by removal of the existing protection group, if appropriate, from compounds containing compounds of the formula Xa ', wherein each time the substituent contains sulfur in the 5-position and the hydroxy group in the 3-position of the cyclic basic set are in a trans position and wherein the R substituent in the 4-position and the hydroxy group in the 3-position of the cyclic base set are each in the cis position.

12. Compounds of the general formula Xa according to claim 11, which contain a secondary nitrogen atom in the cyclic base assembly, which is protected by the protecting group t e r -bu t oxi ca rboni 1 o.

13. Compounds of the general formula Xa according to claim 12, wherein R901 means hydrogen or together with R801 forms an alkylene chain having from 3 to 4 carbon atoms.

14. Use of iodide II - of samarium for the reduction of compounds in 1 to 1 of the general formula Xa of the indication 1.

15. Use of 2-Oxide of (RS) -4 (S) -isopropyl-2-p-toluoyl-4,5-dihydro [1,2-6,3] oxathiazole, 2-oxide of (Ss) -4 (R ) - is op r op i 1 - 2 -p - to 1 uo i 1 - 4, 5 -dihid.ro [1, 2? , 3] oxathiazole 2-oxo-do (Rs) -4 (R) -isopropyl-2-p-toluoyl-4,5-dihydro [1,2-6,3] oxathiazole and 2-oxido (S) ) -4 (R) -isopropyl-2-p-toluoyl-4,5-dih i dr or [1, 2? 6, 3] oxa t ia zo 1, for the stereochemically controlled realization of ring closure reactions for the preparation of azacyclic compounds according to claim 1.

16. Use of [S s, N (1 S)] - N - [1 - [[tert -butyl-dimethyl-silyl) oxy] methyl] -2-methyl-propyl] - S -me ti 1 - S - (4 -me ti 1-f-enyl) s -f-oximin and [RS, N (1R)] -N- [1- [[tert-butyl-dimethyl-silyl] oxy] methyl] -2-methyl-propyl] - S-methyl-S- (4-ethyl-f-nyl) sulfoximine for the stereochemically controlled realization of ring closure reactions for the preparation of azacyclic compounds according to claim 1.