WO2004069847A1 - Nucleoside analogues with apoptosis-inducing characteristics for treating diseases caused by rapidly proliferating cells - Google Patents

Abstract

The invention relates to medicaments and compounds for treating diseases caused by rapidly proliferating cells such as tumour cells, in particular blast cells in children with acute leukaemia. The invention also relates to the production of corresponding medicaments and compounds.

Description

 Nuk.eosidanaloqa with apoptosis-inducing properties for the therapy of diseases caused by highly proliferating cells

The present invention relates to compounds and medicaments for the treatment of diseases caused by highly proliferating cells, and to processes for the preparation of such compounds and medicaments.

The emergence of malignant, semimalignant tumors and other benign hyperproliferative diseases, such as. B. psoriasis or the keloid, is due to a disturbed balance between the formation of new tissue and the regulated death of cells from the tissue composite. In clinical practice, the use of cytotoxic treatment methods such as chemotherapy, radiation therapy and hyperthermia tries to bring this disturbed balance back into balance and to kill the excess tumor cells at the same time. It is generally accepted that most chemotherapeutic agents currently used in clinical practice develop their effects by induction of apoptosis (programmed cell death) (Hannun, 1997). However, some of the patients suffering from malignant tumors develop chemotherapy and radiation resistance at an early stage or are primarily refractory to therapy (Hickman, 1996). It is also known that primary tumors and metastases often respond very differently to cytotoxic therapies. Based on recent studies, it is likely that the cause of resistance lies in different disorders of the apoptosis signal cascade (Raisova et al., 2000).

In particular, the therapy of a relapse of childhood acute lymphoblastic leukemia (ALL), the most common malignancy in childhood, has still not been satisfactorily resolved. So die B. Despite aggressive therapy, about 70% of the children with illness in the relapse of ALL. The same applies to others, some of which are difficult to treat

BESTÄT1GÜWOSI 0PIE Tumor diseases such as thyroid carcinoma, very common breast cancer, difficult to access medulloblastoma or towards gliomas. A benign skin condition that is also treated with such therapies is psoriasis (psoriasis). It is one of the most common skin diseases that affect two to four percent of people. The therapy for this disease is also in great need of improvement.

WO 2080923 AI describes nucleoside analogues that trigger apoptosis and have a cytostatic effect. These compounds have in common a ring structure which contains a diene system to which an iron tricarbonyl is preferably coordinatively bound. Because of the diene structure, the known substances are difficult to synthesize. The substances tend to undesirable side reactions due to the reactivity of the diene and are therefore relatively unstable. This is disadvantageous both for storage and preparation in connection with other pharmaceutical components, and for the specificity after administration.

Numerous other nucleoside analogs with biological activity are disclosed in WO 02/100354 and EP0468352 A2.

Velcicky et al., 2002, discloses a general synthetic strategy for nucleoside analogs using targeted protecting groups. According to the authors, the synthesis should make it possible to produce a large variety of nucleoside analogues that could potentially have biological activity. In this context, reference is made to the biological activity of the known carbocyclic nucleoside analogues carbovir and abacavir. Only the racemates, but not the enantiomers, are obtainable from the syntheses described.

In Tetrahedron Letters, Vol. 34, No. 18, pp. 2993-2994, 1993, modifications in the carbohydrate chain of pyrimidine nucleosides are reported. The compounds disclosed therein are said to have anti-HIV activity in vitro. In Tetrahedron Vol. 51, No. 7, pp. 2029-2038, 1995, it is reported that 2 ', 3'-dideoxy-cyclo-2'-pentenyl-3'-C-hydroximethylcarbocyclic

Nucleoside analogues have an antiviral potential.

In Tetrahedron Vol. 49, No. 44, pp. 10061-10068, 1993, a new synthesis of 2 ', 3'-dideoxy-2', 3 ', - didehydro-3'-C-substituted thymidines is disclosed. Such compounds have inhibitory effects on HIV reverse transcriptase.

EP-A-0 358 154 discloses cyclobutane derivatives and a process for their preparation.

FR-A-2 662 165 discloses branched nucleoside derivatives, a process for their preparation and their use in a medicament.

There is a strong need to develop substances and drugs that improve the healing success and survival of patients suffering from the diseases listed above. In the case of tumor diseases and leukaemias in particular, it is important to provide new drugs that are highly selective against unnaturally proliferating cells and thereby attack healthy cells as little as possible. In addition, it is of particular importance to provide therapeutic substances against those tumors which have proven to be resistant to known substances. The invention is therefore based on the object of providing corresponding substances. Another task is to provide substances with alternative and new mechanisms of action in order to expand and supplement the treatment options. The invention is also based on the object of providing corresponding substances which are simple to manufacture and are relatively stable.

Surprisingly, the object on which the invention is based is achieved by compounds according to claims 1 to 5 and medicaments according to claims 6 to 9, a process for the preparation of Medicaments according to claim 10 and synthesis methods according to claims 11 and 12.

The invention does not relate to the compounds described in Velcicky et al. (2002). The subject of the invention, however, are, as far as claimed, corresponding medicaments. In their purely synthetic work, the authors did not recognize that some of the products and intermediate products disclosed are themselves particularly suitable for the treatment of tumors.

The invention relates to the various stereoisomers of the compounds according to the invention, the individual enantiomers and the corresponding racemates. The cis configuration in the compounds according to the invention denotes that the radicals Y and Z are on the same side of the central five-membered ring.

The compounds according to the invention can be used to prepare a medicament for the treatment of malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating tumors or skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin's and non-Hodgkin's lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, as well as for antibacterial, antifungal, anti-protozoa, anti-plasmodia, anti-helminthic, antiviral or immunosuppressive therapy.

The pharmaceuticals and compounds according to the invention are unexpectedly suitable for the therapy of pathologically rapidly proliferating tissue, in particular bone marrow, but also of solid tumors, such as epithelial tumors or in particular brain tumors. Furthermore, the applicability of the substances described also extends to the treatment of benign, hyperproliferative diseases of the skin, such as, for. B. the psoriasis or the keloid. The drugs and substances of the invention are characterized in that they are particularly suitable, selectively that Inhibit growth of highly proliferating cells. As a result, they initiate apoptosis of highly proliferating cells and thus destroy them, with healthy cells being affected very little. The experiments carried out show that substances according to the invention trigger apoptosis unusually quickly. The experiments carried out suggest that apoptosis could be initiated using a new mechanism.

The substances are particularly preferably membrane-permeable, which leads to a high intracellular active substance concentration. The high effectiveness is therefore likely to be achieved through the pronounced lipophilicity of the substances. The substances differ fundamentally from known nucleoside analogues used for therapy, such as cytarabine, cladribine and fludarabine 5'-dihydrogen phosphate. They are able to break existing cytostatic resistances.

The pharmaceuticals and compounds of the invention are particularly suitable for the treatment of tumor diseases and leukemia. They induce apoptotic cell death not only in permanent cell lines (BJAB cells) formed from tumor cells, but also in primary cells from patients with acute lymphoblastic leukemia (ALL). This allows the substances according to the invention against tumor diseases of the bone marrow, but also against tumors of another provenance, such as. B. epithelial tumors, sarcomas or malignant diseases of the skin, etc. are used.

In special embodiments, the developed substances are able to cross the blood-brain barrier unhindered due to their lipophilicity. Therefore, they can be used to treat malignant brain tumors, such as, for. B. the medulloblastoma or gliomas can be used. Overall, the substances according to the invention can be used to treat malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semi-malignant rapidly proliferating skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, as well as inflammatory and chronic inflammatory diseases. They are also suitable for antiviral, antibacterial, antifungal, anti-protozoa, anti-helminthic or immunosuppressive therapy.

The compounds and medicaments of the invention have the advantage over the known substances from WO02 / 080923 that they are easier to synthesize, handle and store, and have little tendency to undesirable side reactions in the preparation of the medicament and also in the body.

1 shows that the novel nucleosides show a cytotoxicity of up to 85% in BJAB cells at a concentration in the cell culture medium of 30 μmol / l. Here, cell death is measured by the release of lactate dehydrogenase (LDH) after 48 hours, which can only leave the cell's cytoplasm after damage to the cell membrane. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations <3%). The results are shown for the substances (-) - 159a to d and (-) - 113b.

2 shows that the cell death triggered by the novel nucleoside analogs is not undifferentiated necrosis but apoptosis. The measurement of apoptosis is based on a method that demonstrates the fragmentation of DNA typical of apoptosis at the individual cell level, which distinguishes this cell death form from necrosis. For this purpose, BJAB cells were treated for 72 h with a concentration of 20 μmol / l of different nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured the mean value given was confirmed after two independent repetitions of the experiment (deviations <3%).

However, the substances have a proapoptotic effect not only on permanent cell lines, but also on lymphoblasts obtained directly from children with an ALL (FIG. 3). In contrast to the already known and widely used chemotherapeutic agents, such as epirubicin or cytosine arabinoside, the novel nucleoside analogs tested also initiate apoptosis in therapy-resistant patient cells in vitro (data not shown). FIG. 3 shows apoptosis induction via the resulting DNA fragmentation on primary lymphoblasts - of children with acute lymphoblastic leukemia (ALL). After isolation of the primary lymphoblasts and dilution with cell culture medium, they were treated with 20 μM each of the nucleoside analog for 36 h. Controls contained appropriate amounts of the solubilizer ethanol. After the treatment, the fragmentation of the DNA was stained with propidium iodide and then quantified by flow cytometry as described by Eßmann et al. (2000). The values are given as% apoptotic cells of the total population. Duplicate values were measured, the mean value being confirmed after two independent repetitions of the experiment (deviations <3%).

The sequence of apoptosis leads to the activation of a family of cysteine proteases, the so-called caspases, which dissolve the cell from the inside during the ongoing death program (Cohen, 1997). In order to investigate the specificity of the substances according to the invention in more detail, the processing and activation of caspase-3, caspase-8 and caspase-9 was detected using the Western blot technique (FIG. 4). For this purpose, BJAB cells were treated for 36 h with a concentration of 20 μmol / l of the nucleoside analogs. Controls contained appropriate amounts of the solubilizer ethanol (EtOH). After treatment, the processing of Procaspase-3, Pro-C-8 and Pro-C-9 became more specific Immunodetection in a Western blot as described by Eßmann et al. (2000). The positions of the procaspases and the processed subunits in the SDS-polyacrylamide gel are indicated by dashes on the left edge of FIG. 4. The addition of 20 μmol / l of the substances to the medium of BJAB cells triggers a processing of the Procaspasen-3, -8 and -9 in these cells. The specific, immunochemical detection of the active subunits of caspases-3, -8 and -9 in treated cells can be seen in contrast to the corresponding control cells. The result makes it clear that the substances according to the invention specifically induce an apoptotic cascade. The nucleoside analogue (-) - 159b induces the caspase processing (FIG. 4) so quickly that even at the time of measurement after 36 h hardly any of the procaspases-3, -8 and -9 are present.

5 already contains a first indication of the apoptosis signal cascade activated by the novel nucleoside analogs. 5 shows that the BJAB cells incubated with the novel nucleoside analogs over 48 h are driven into the mitchondrial apoptosis pathway. This was visualized by staining the cells with the mitochondrial specific ^'ifischen dye JC-1, such as by re et al. (2001). Incubation of the cells with the new nucleoside analogues led to a significant increase in the proportion of cells with a reduced mitochondrial, membrane potential (ΔΨ _m ) from 5% in the control to 80%, which indicates a strong activation of the mitochondria during the apoptotic process indicates (Fig. 5).

The compound racx4 (FIG. 6) shows an apoptosis of approximately 42% at a concentration of 100 μg / ml.

The usability of the substances according to the invention for the therapy of various malignant diseases of the hematopoietic system has been successfully tested in vitro on cells from patients with different diseases. The substances of general structural formula 2 are thus effective as agents against certain tumor cells, particularly those of childish ALL, but also against other malignant diseases of different origins.

The medicaments according to the invention can be administered topically or intravenously. In the case of intravenous administration, the substances are administered in the concentration range between 0.1 to 100 μg / ml, based on the patient's blood volume. The substances are rubbed into the diseased skin in a concentration of 0.1 to .5% by weight, based on the finished preparation.

Rule Svnthese

NB = nucleobase 1.) H ₃ 0 ⁺

R = ThxMe ₂ Si, f-BuPh ₂ Si

2.) R-Cl

General one-pot reaction for hydrolysis and silylation

(-) - 100 (+) - 95 and (+) - 155

(+) - 95 R = ThxMe ₂ Si (+) - 155 R = f-BuPh ₂ Si (+) - 95 R = ThxMe ₂ Si a (R '= H, X = OH) a (R' = Br, X = OH) e (X = OCONPh ₂ , Y = NHAc) b (R '= F, X = OH) b (R' = F, X = OH) c (R '= Me, X = OH) c ( R '= H, X = NHBz) (+) - 155 R = fr-BuPh ₂ Si d (R' = H, X = NHBz) d (X = OCONPh ₂ , Y = NHAc)

The racemic precursors of the rac-100 type are prepared by known methods (see WO 02/080923 and Velcicky et al., 2002). To produce the optically active compounds, as explained in WO 02/080923, either the chirogenic step of the synthesis (Pauson-Khand reaction) is carried out enantioselectively, or a racemate resolution is carried out at a subsequent stage. In general, the following reactions can be carried out by individual enantiomers or by the racemate. A solution of lOOa-e (lmmol) and PPTS (76 mg, 300 μmol, 30 mol%) in absolute acetone (10 ml) was stirred under reflux for 3 h. The solvent was removed and the vessel was flushed three times with argon. Then 3 ml of absolute pyridine were added and after stirring for 5 min. at RT ThxMe ₂ SiCI (310 μl, 1.5 mmol, 1.5 equiv.) or t-BuPh ₂ SiCl (79 μl, 300 μmol, 1.5 equiv. for 200 μmol of 100) added. After stirring at RT for 16 h, the reaction mixture was quenched with saturated aqueous NaHCO ₃ solution (20 ml). After stirring for 30 min. at RT the aqueous phase was extracted with EtOAc (4 x 20 ml) and the collected organic phases with 10% aqueous HCL solution. (3 x 20 ml), more saturated aqueous NaHCO ₃ solution. (20 ml) and NaCl solution. (40 ml), dried over MgSO ₄ and freed from the solvent by distillation. The residue was purified by flash chromatography.

Preparation of (+) - (3 /?, 5S) -5- [Dimethyi- (l, l, 2Hrrimethyl-propyl) - silanyloxy] -3- (2 ', 4' -dioxo-3 ', 4' -dϊhydro -2 f-pyrimidine-1'-yl) - cyclopent-1-encarbaldehyde (95a)

The compound (+) - 95a was obtained according to the general test instructions as a clear liquid (309 mg, 82% yield).

rn.p. = 115-116 ° C (EtOAc / CyHex).

TLC: R _f = 0.24 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +59.3 (c 0.62, CHCI ₃ ), [ä] ₅₄ 6 ²⁰ = +72.2, [ä] ₄ o ₅ ²⁰ = +169.6, [ä] ₃ 6 ₅ ²⁰

= +223.6. H NMR (250 MHz, CDCI ₃ ): δ = 9.85 (s, IH, HC = O); 8.78 (bs, IH, NH); 7.47 (d, = 8.0, IH, H-6 '); 5.56 (dd, = J ₂ = 2.2, IH, H-2); 5.90 (dddd, = 9.5, j ₂ = 7.1, J ₃ = J ₄ = 2.2, IH, H-3); 5.71 (dd, = 8.0, J ₂ = 2.4, IH, H-5 '); 4.27 (dd, = 10.0, J ₂ = 3.0, IH, SiOCHa); 3.58 (dd, = 10.0, J ₂ = 2.5, IH, SiOCHb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J ₂ = J ₃ = 9.5, IH, H-4a); 1.82 (ddd, =, 14.2, J ₂ = J3 = 7.5, IH, H-4b); 1.56 (septet, J = 6.8, IH, Me ₂ CH); 0.81 (d, J = 6.8 Hz, 6H, (CH ₃ ) ₂ CH); 0.788 + 0.786 (2s, 6H, C (CH _{3) 2);} 0.042 + 0.036 (2s, 6H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.9 (CH = O), 163.2 (C4 '), 150.8 (C2'), 150.3 (Cl), 147.8 (C2), 141.4 (C6 '), 103.2 ( C5 '), 62.2 (CH ₂ OSi), 58.9 (C3), 44.3 (C5), 34.0 Me ₂ CH), 33.3 (C4), 25.4 (Me ₂ CSi), 20.3 and 20.2 ((CH ₃ ) ₂ CH) , 18.5 and 18.4 ((CH ₃ ) ₂ CSi), -3.5 and -3.6 ((CH ₃ ) ₂ Si).

IR (ATR, cm ^"1 ): = 3038 (w, NH), 2955 (m, CH), 2865 (w, CH), 1697 (s, C = O), 1680 (s, C = O), 1649 (s, C = C), 1473 (w), 1445 (w), 1425 (w), 1383 (m), 1276 (m), 1248 (m, CO), 1186 (m), 1111 (m), 1063 (w), 1019 (w), 998 (w), 979 (w), 849 (m), 828 (m), 804 (m), 779 (m), 761 (m). MS (EI, 70 eV): m / z (%): 295 (7), 294 (17), 293 (100) [M-85] ⁺ , 275 (27), 250 (18), 201 (55) , 181 (62), 169 (26), 151 (8), 137 (5), 99 (7), 91 (5), 89 (7), 85 (6), 77 (6), 75 (23) , 73 (18), 69. (6), 59 (8), 57 (5). HRMS (EI) C ₁₃ H ₁₇ N ₂ O ₄ Si [M-85] ⁺ : calcd. 293,096, found: 293,096.

Preparation of (-) - (3S, 5Ä) -5- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3- (2 ', 4' -dioxo-3 ', 4' -dihydro -2f / -pyrimidine-l'-yl) ~ cyclopent-l-encarbaldehyde (95a)

Compound (-) - 95a was obtained as a clear liquid (264 mg, 70% yield) according to the general experimental procedure.

[ä] _D ²⁰ = -55.5 (c 0.45, CHCI ₃ ), [ä3 ₅₄₆ ²⁰ = -67.7, [ä] ₄₀₅ ²⁰ = -159.0, [ä] ₃ 6 ₅ ²⁰ = -209.3.

Preparation of (+) - (3 /?, 5S) -3- (5 '-Fluor-2', 4 '-dioxo-3, 4' -dϊhydro- 2 -pyrimidin-l '-yl) -5- [ dimethyl- (l _Λ l, 2-trimethyl-propyl) -silanyloxy] - cyclopent-1-encarbaldehyde (95b)

Compound (+) - 95b was obtained as a clear liquid according to the general experimental procedure (173 mg, 74% yield).

m.p. = 148-149 ° C (EtOAc / Hex).

TLC: R _f = 0.50 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +53.6 (c 0.50, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +65.2, [ä] ₄ o ₅ ²⁰ = +148.5, [ä] ₃₆₅ ²⁰

= +186.9.

^X W MMR (250 MHz, CDCI ₃ ): δ = 9.86 (s, IH, HC = 0); 9.06 (bs, IH, NH); 7:55

(d, 3 = 5.6, IH, H-6 '); 6.56 (dd, = J ₂ = 2.1, IH, H-2); 5.90 (m, IH, H-3);

4.29 (dd, = 10.1, J ₂ = 2.9, IH, SiOCHa); 3.58 dd, = 10.1, J ₂ = 2.2, IH,

SiOC / Vb); 3.18 (m, IH, H-5); 2.79 (ddd, = 14.2, J ₂ = J ₃ = 9.4, IH, H-4a);

1.82 (ddd, = 14.3, J ₂ = J ₃ = 6.7, IH, H-4b); 1.57 (septet, J = 6.8, IH, Me ₂ CH); 0.82 (d, J = 7.4, 6H, (CH ₃ ) ₂ CH); 0.798 + 0.794 (2s, 6H, C (CH _{3) 2);} 0.06 (s, 6H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.7 (CH = O), 156.6 (d, J _C , _F = 27, C4 ^' ), 150.6 (C2'), 149.3 (Cl), 147.0 (C2) , 145.0 (d, J _C , _F = 269, C5 '), 125.2 (d, J _C , _F = 32, C6'), 62.3 (CH ₂ OSi), 59.4 (C3), 44.3 (C5), 34.0 ( Me ₂ CH), 32.9 (C4), 25.5 (Me ₂ CSi), 20.4 and 20.2 ((CH ₃ ) ₂ CH), 18.44 and 18.37 ((CH ₃ ) ₂ CSi), -3.4 and -3.6 (CH ₃ Si ).

IR (ATR, cm ^"1 ): = 3160 (w, NH), 3049 (m, NH), 2955 (m, CH), 2866 (m, C-H), 2830 (w), 1720 (s, C = O), 1711 (s, C = O), 1685 (s, C = O), 1657 (s, C = C), 1468 (m), 1390 (m), 1384 (m), 1379 (m) , 1348 (f), 1273 (m), 1267 (m), 1248 (s, CO), 1203 (f), 1183 (m), 1155 (m), 1110 (s), 1058 (m), 1015 ( m), 995 (w), 983 (m), 889 (m), 872 (m), 830 (s), 780 (s), 743 (m), 725 (w), 704 (m), 668 ( w).

MS (EI, 70 eV): m / z (%): 863 (2), 825 (6), 755 (2), 555 (5), 529 (8), 445 (13), 413 (100), 409 (56), 397 [M + H] ⁺ (49), 387 (4), 267 (6), 251 (25), 237 (14), 181 (2), 121 (5), 107 (8) ,

Preparation of (-) - (3S, 5 /?) ~ 3- (5 '-fluoro-2', 4 '-dioxo-3', 4 ^' -dihydro-2r / -pyrimidin-l' -yl) -5 - [dimethyl- (ll _Λ 2-trimethyl-propyl) -siIanyIoxy] - cyclopent-1-encarbaldehyde (95b)

Compound (-) - 95b was obtained as a clear liquid according to the general experimental procedure (171 mg, 73% yield)

[ä] _D ²⁰ = -53.3 (c 0.52, CHCI ₃ ), [ä3 ₅ 6 ²⁰ = -65.2, [a] ₄₀₅ ²⁰ = -148.4, [ä] ₃₆₅ ²⁰ = -187.4.

Representation of (+) - (3Λ, 5S) -5- [dimethyl- (ll, 2-trimethyI-propyI) - silanyloxy] -3- (5'-methyl-2 ' _/ 4' -dϊoxo-3 '4 - dihydro-2H-pyrimidine

1'-yI) -cyclopent-l-encarbaldehyde (95c) Compound (+) - 95c was obtained as a clear liquid according to the general experimental procedure (252 mg, 64% yield).

m.p. = 58-61 ° C (EtOAc / CyHex).

TLC: R _f = 0.26 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +28.8 (c 0.53, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +35.4, [ä] ₄₀ 5 ²⁰ = +104.1, [ä] ₃₆₅ ²⁰

= +173.7. NMR (250 MHz, CDCI ₃ ): δ = 10.06 (bs, IH, NW); 9.81 (s, IH, HC = O); 6.99

(q, J = 1.2, IH, H-6 ^' ); 6.58 (m, IH, H-2); 5.83 (dddd, = J ₂ = 8.6, J ₃ = J ₄ =

2.4, IH, H-3); 4.18 (dd, = 10.0, J ₂ = 3.4, IH, SiOCb / a); 3.53 (dd, =

10.0, J ₂ = 2.4, IH, SiOCHb); 3.10 (m, IH, H-5); 2.65 (ddd, = 13.4, J ₂ = J ₃

= 8.8, IH, H-4a); 1.85 (d, J = 1.2, 3H, CH _3); 1.80 (ddd, = 13.4, J ₂ = J ₃ =

8.4, IH, H-4b); 1.51 (septet, J = 7.1, IH, Me ₂ CH); 0.83 (d, J = 7.1, 6H,

(CH ₃ ) ₂ CH); 0.793 + 0.790 (2s, 6H, C (CH _{3) 2);} 0.058 + 0.057 (2s, 6H, S \ CH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.9 (CH = O), 164.1 (C4 '), 151.1 (C2'),

149.8 (Cl), 148.4 (C2), 136.2 (C6 '), 111.8 (C5'), 61.4 (CH ₂ OSi), 59.0 (C3),

44.2 (C5), 34.0 (Me ₂ CH), 33.4 (C4), 25.1 (Me ₂ CSi), 20.2 and 20.2 ((CH ₃ ) ₂ CH),

18.4 and 18.4 ((CH ₃ ) ₂ CSi), 12.3 (CH ₃ ), -3.5 and -3.7 (SiCH ₃ ).

IR (ATR, cm ^"1 ): = 3177 (w, NH), 3050 (w, NH), 2954 (m, CH), 2864 (m, C-

H), 1683 (s, C = O), 1464 (m), 1376 (m), 1279 (m), 1249 (m, C-O), 1153 (w),

1113 (m), 1057 (w), 1017 (w), 982 (w), 874 (m), 830 (m), 778 (m), 722 (w).

MS (EI, 70 eV): m / z (%): 393 (4) [M + l] ⁺ , 365 (13), 341 (5), 307 (100), 289

(27), 264 (10), 215 (52), 183 (31), 181 (73), 167 (12), 151 (7), 137 (5), 113

(4), 89 (7), 75 (15), 59 (4).

HRM (ESI) C ₂₀ H ₃₃ N ₂ O ₄ Si [M + 1] ⁺ : calcd 393.2209, found 393.2209.

Preparation of (-) - (3S, 5R) -5- [dimethyl- (l, l, 2-trϊmethyl-propyl) -silanyloxy] -3- (5'-methyl-2 4 '-dioxo-3', 4 '-dihydro-2J -pyrimidine-

1 '-yl) -cyclopent-1 ~ encarbaldehyde (95c) Compound (-) - 95c was obtained as a clear liquid (235 mg, 60% yield) according to the general experimental procedure.

[ä] _D ²⁰ = -23.6 (c 0.54, CHCI ₃ ), [ä] ₅₄ 6 ²⁰ = -29.4, [ä] ₄₀₅ ²⁰ = -88.2, [ä] ₃₆₅ ²⁰ = -146.9.

Preparation of (+) - (3K, 5S) - / V- (l- {4- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3-formyl-cyclopent-2-enyl> - 2 '-oxo-1', 1 '- dϊhydro-pyrimidin-4' -yl) -benzamide (95d)

Compound (+) - 95d was obtained as a light yellow liquid (324 mg, 67% yield) according to the general experimental procedure.

m.p. = 78-81 ° C (EtOAc / CyHex).

TLC: R _f = 0.28 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +59.5 (c 0.59, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +70.5, [ä] ₄₀₅ ²⁰ = +97.5.

^X H NMR (250 MHz, CDCI ₃ ): δ = 9.88 (s, IH, HC = O); 8.23 (bs, IH, NH); 7.89

(d, J = 6.3, 3H, H-6 ^' + 2H-Ph); 7.63-7.46 (m, 4H, H-5 '+ 3H-Ph); 6.63 (t, J =

2.1, IH, H-2); 6.10 (m, IH, H-3); 4.26 (dd, = 10.0, J _z = 3.2, IH, SiOCHa);

3.59 (dd, = 10.0, J ₂ = 2.3, IH, SiOCHb); 3.22 (m, IH, H-5); 2.90 (ddd, =

14.0, J ₂ = J ₃ = 9.3, IH, H-4a); 1.84 (ddd, J _α = 14.0, J ₂ = J ₃ = 6.7, IH, H-4b);

1.57 (septet, J = 6.8, IH, Me ₂ CH); 0.82 (d, J - 6.9, 6H, (CH ₃ ) ₂ CH); 0.80 (s,

6H, C (CH ₃ ) ₂ ); 0.05 (s, 6H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.9 (CH = O), 161.9 (C = O (Bz)), 150.4

(C2 ^' ); 147.9 (C6 ') 146.1 (C2), 133.3 and 129.0 and 127.6 (all from Ph),

62.3 (CH ₂ OSi), 60.6 (C3), 44.5 (C5), 34.3 (C4), 33.0 (Me ₂ CH), 25.4 (Me ₂ CSi),

20.4 and 20.2 ((CH ₃ ) ₂ CH), 18.5 and 18.4 ((CH ₃ ) ₂ CSi), -3.47 and -3.49 (Si (CH ₃ ) ₂ ).

IR (ATR, cm ^"1 ): = 3230 (w, NH), 3142 (w, NH), 3061 (w, NH), 2954 (m, CH), 2864 (m, CH), 1684 (s, C = O), 1661 (s, C = N), 1622 (s, C = C), 1554 (m), 1484 (s), 1376 (m), 1309 (m), 1249 (s, CO), 1181 (m), 1107 (m), 1070 (w), 1001 (w), 978 (w) , 844 (m), 830 (m), 802 (m), 780 (m), 705 (m); MS (ESI, 70 eV): m / z (%): 1241 (21), 1209 (34), 1177 [2M + Na] ⁺ (11), 632 (49), 610 [M + Na] ⁺ (100 ), 600 (27), 578 [M + H] ⁺ (27), 484 (2), 417 (2), 238 (6), 216 (57), 121 (2), 105 (4).

Preparation of (-) - (3S, 5Λ) - / V- (l- {4- [dimethyl- (l, l, 2-trimethylpropyl) -sϊlanyloxy] -3-formyl-cyclopent-2-enyl} - 2'-oxo-1 ', 1' - dihydro-pyrimidin-4 '-yl) -benzamide (95d)

Compound (-) - 95d was obtained as a yellow liquid according to the general experimental procedure (316 mg, 66% yield).

[ä] _D ²⁰ = -47.1 (c θ.32, CHCI ₃ ), [ä] ₅₄ 6 ²⁰ = -56.3, [ä] ₄₀₅ ²⁰ = -64.4.

Preparation of (+) - (3 /?, 5S) -diphenyI-carbamic acid 2'-acetylamino-9 '- (4- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxy] -3- formyl-cycIopent-2-enyI} -9Af-purin ~ 6 '-yl ester (95e)

Compound (+) - 95e was obtained as a light yellow liquid according to the general experimental procedure (895 mg, 68% yield).

m.p. = 79-84 ° C (EtOAc / CyHex).

TLC: R _f = 0.33 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +5.7 (c 0.37, CHCI ₃ ), [ä] ₅ 46 ²⁰ = +5.7, [ä] ₄₀₅ ²⁰ = -28.5, [ä] _36S ²⁰ = -

110.1.

^X H NMR (250 MHz, CDCI ₃ ): δ = 9.88 (s, IH, HC = O); 8.06 (s, IH, H-8 ^' ); 7.99 (s, IH, N / A); 7.40-6.72 (m, 10H, 2 x Ph); 6.72 (s, IH, H-2); 5.82 (m, IH, H-3); 4.17 (dd, = 8.5, J ₂ = 3.5, IH, SiOCHa); 3.69 (dd, = 8.3, J ₂ = 2.3, IH, SiOCHb); 3.27 (m, IH, H-5); 2.89 (ddd, = 11.5, J ₂ = J3 = 7.5, IH, H-4a); 2:52 (s, 3H, CH ₃ CO); 2.12 (ddd, = 11.5, J ₂ = J ₃ = 6.0, IH, H-4b); 1:56 (septet, J = 6.8, IH, Me ₂ CH); 0.81 (d, J = 6.9, 6H, (CH ₃ ) ₂ CH); 0.79 (s, 6H, C (CH _{3) 2);} 0.05 (s, 6H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 189.1 (CH = O), 170.6 (CH ₃ C = O), 154.7 (C4 '), 156.3 and 152.1 and 150.4 (C4' + C6 '+ Ph ₂ NC = O), 149.7 (Cl), 146.8 (C2), 142.1 (C8 '), 141.7 and 129.1 and 127.0 (br) (all of Ph), 120.6 (C5'), 62.2 (CH ₂ OSi), 57.9 (C3 ), 44.7 (C5), 35.0 (C4), 34.0 (MezCH), 25.3 (Me ₂ CSi), 25.0 (CH ₃ C = O), 20.35 and 20.29 ((CH ₃ ) ₂ CH), 18.45 and 18.43 (( CH ₃ ) ₂ CSi), -3.55 (Si (CH ₃ ) ₂ ).

IR (ATR, cm ^"1 ): = 3272 (w, NH), 3060 (w, NH), 2954 (m, CH), 2864 (w, C-H), 1740 (s, C = O); 1685 (s, C = O), 1617 (s, C = C), 1586 (s), 1490 (s), 1444 (m), 1374 (s), 1334 (s), 1280 (s, CO), 1214 (s), 1186 (s), 1167 (s), 1109 (m), 1059 (s), 1032 (m), 1002 (s), 931 (w), 907 (m), 873 (m), 830 (s), 779 (m), 757 (m), 739 (m), 699 (s), 643 (m).

Preparation of (-) - (3S, 5R) -DϊphenyI-carbamic acid 2 '-acetylamino-9' - {4- [dϊmethyl- (l, l 2-trimethyl-propyl) -silanyloxy] -3-formyl-cyclopent -2-enyl} -9A -purin- 6 '-yl ester (95e)

Compound (-) - 95e was obtained as a light yellow liquid according to the general experimental procedure (877 mg, 67% yield).

[ä] _D ²⁰ = -7.0 (c 0.60, CHCI3). [ä] ₅₄₆ ²⁰ = -7.4, [a] ₄₀₅ ²⁰ = +27.5, [ä] ₃₆₅ ²⁰ = + 112.6.

Representation of (+) - (3R, 5S) -3- (5 ^' -Fluor-2' 4 '-dιoxo-3', 4 '-dihydro-

2- -pyrimidϊn-l '-vl) -5- (£ ^_ ert - 3utyl-diphenyI-siIanyI-oxvmethyl) - cvclopent-l-encarbaldeh d (155a)

The compound (+) - 155a was obtained as a clear liquid according to the general experimental procedure (29 mg, 59% yield).

TLC: R _f = 0.49 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +63.0 (c 0.56, CHCI3); [ä] ₅₄₆ ²⁰ = +76.5, [ä] ₄₀₅ ²⁰ = +178.6, [ä] ₃₆₅ ²⁰

= +250.4. ^X NMR (250 MHz, CDCI ₃ ): δ - 9.88 (s, IH, HC = O); 9.67 (bs, IH, NH); 7.56 (d, J = 5.9, 4H, Ph); 7.45-7.31 (m, 6H, Ph); 7.29 (d, J = 5.5, IH, H-6 '); 6.61 (dd, = J ₂ = 2.1, IH, H-2); 5.86 (dd, = J ₂ = 7.7, IH, H-3); 4.23 (dd, = 10.3, J ₂ = 4.1, IH, SiOCHa); 3.74 (dd, = 10.3, J ₂ = 2.7, IH, SiOCHb); 3.19 (m, IH, H-5); 2.76 (ddd, = 13.9, J ₂ = J ₃ = 9.0, IH, H-4a); 1.85 (ddd, = 13.9, J ₂ = J ₃ = 7.7, 1 ^' H, H-4b); 1.02 (s, 9H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.6 (CH = O), 156.8. (d, J _C , _F = 27, C4 '), 150.6 (C2'), 149.5 (Cl), 146.8 (C2), 140.9 (d, J _{C / F} = 241, C5 '), 135.6 and 135.4 and 133.1 and 132.8 and 129.9 and 127.78 and 127.76 (all of Ph), 124.8 (d, J _C , _F = 33, C6 '), 62.9 (CH ₂ OSi), 59.8 (C3), 44.3 (C5), 33.3 ( C4), 26.9 ((CH ₃ ) ₃ CSi), 19.3 (Me ₂ CSi).

IR (ATR, cm ^"1 ): = 3181 + 3166 (w, NH), 3065 (m, NH), 2952 + 2927 (m, CH), 2883 (w, CH), 2853 (m, CH), 1714 (s, C = O), 1683 (s, C = O), 1587 (w), 1468 (m), 1425 (m), 1382 (m), 1341 (m), 1273 (m), 1243 (s , CO), 1186 (m), 1153 (m), 1107 (s), 1057 (m), 1015 (w), 995 (w), 984 (w), 935 (w), 888 (m), 851 (w), 821 (m), 786 (m), 742 (m), 702 (s).

MS (EI, 70 eV): m / z (%): 1055 (2), 1039 (3), 1023 [2M + K] ⁺ (2), 1007 [2M + Na] ⁺ (1), 547 (100 ), 515 [M + Na] ⁺ (14), 493 [M + H] ⁺ (2), 429 (21), 415 (11), 285 (5), 251 (6), 219 (2), 167 (4), 121 (5).

Representation of (+) - (3K, 5S) -3- (5 '-Brom-2', 4 '-dioxo-3', 4'-dihydro-

2H-pyrimϊdin-l '-yl) -5- (tert-butyl-diphenyl-silanyloxymethyl) - cyclopent-1-encarbaldehyde (155b)

Compound (+) - 155b was obtained according to the general experimental procedure as a clear liquid (55 mg, 50% yield), (76% yield as a racemic mixture).

m.p. = 121-123 ° C (EtOAc / CyHex).

TLC: R _f = 0.53 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +101.4 (c 0.31, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +122.4, [ä] ₀₅ ²⁰ = +311.5,

[ä] ₃₆₅ ²⁰ = +472.4, [ä] ₃₃₄ ²⁰ = +518.2. ^X H NMR (250 MHz, CDCI ₃ ): δ = 9.90 (s, IH, HC = O); 8.50 (bs, IH, NH); 7.59 - 7.32 (m, 10H, Ph), 7.46 (s, IH, H-6 ^' ); 6.62 (dd, J ₁ = J ₂ = 2.1, IH, H-2); 5.81 (dddd, = J ₂ = 2.5, J ₃ = = 8.4, IH, H-3); 4.20 (dd, = 10.3, J ₂ = 4.4, IH, SiOCHa); 3.74 (dd, J ₁ = 10.3, J ₂ = 2.6, IH, SiOCHb); 3.18 (m, IH, H-5); 2.74 (ddd, = 13.4, J ₂ = J ₃ = 8.7, IH, H-4a); 1.85 (ddd, J ₁ = 13.6, J ₂ = J ₃ = 8.2, IH, H-4b); 1:03 (s, 9H, S _CH3).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.8 (CH = O), 159.3 (C4 ^' ), 150.40 and 150.35 (Cl and C2'), 147.1 (C2), 139.9 (C6 ^' ), 135.5 and 135.3 and 133.0 and 132.8 and 129.8 and 129.4 and 127.7 and 127.6 (all of Ph), 97.8 (C5 '), 62.5 (CH ₂ OSi), 60.1 (C3), 44.3 (C5), 34.0 (C4), 26.9 ((CH ₃ ) ₃ CSi), 19.3 (Me ₂ CSi).

IR (ATR, cm ^"1 ): = 3177 and 3067 and 3048 (w, NH), 2953 and 2928 (m, C-H), 2888 (m, CH), 2854 (w, CH), 1704 (s, C = O), 1683 (s, C = O), 1619 (m, C = C), 1588 (w), 1470 (m), 1443 (m), 1426 (m), 1389 (w), 1362 ( m), 1337 (w), 1276 (m), 1261 (m), 1242 (m, CO), 1209 (w), 1189 (w), 1151 (w), 1110 (s), ^' 1060 (m) , 1037 (m), 1018 (w), 997 (m), 983 (m), 940 (w), 909 (w), 841 (m), 821 (m), 741 (m), 701 (m) ,

Preparation of (+) - (3?, 5S) -. V ~ [l- [4- (-rer £ -butyl-diphenyl-silanyloxymethyl) -3-formyl-cyclopent-2-enyl] -2 ^' -oxo- l ^' , 2 ^' -dihydro-pyrimidin-4 '-yl> -benzamide (155c)

Compound (+) - 155c was obtained as a pale yellow liquid (52 mg, 57% yield) according to the general experimental procedure.

m.p. = 104-108 ° C (EtOAc / CyHex).

TLC: R _f = 0.25 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +45.1 (c θ.32, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +52.6, [ä3 ₄₀₅ ²⁰ = +42.2.

^X NMR (250 MHz, CDCI ₃ ): δ = 9.89 (s, IH, HC = O); 7.88 (d, J = 7.2, 2H, H-

6 ^' + 1H-Ph); 7.63 (d, J = 7.4, IH, H-5 ^' ); 7.60-7.33 (m, 14H, Ph); 6.66 (s,

IH, H-2); 6.07 (m, IH, H-3); 4.28 (dd, = 10.3, J ₂ = 3.9, IH, SiOCHa);

3.74 (dd, = 10.1, J ₂ = 2.7, 1Η, SiOCHb); 3.24 (m, 1Η, Η-5); 2.92 (ddd, = 14.2, J ₂ = J ₃ = 9.3, IH, H-4a); 1.90 (ddd, = 14.2, J ₂ = J ₃ = 7.1, IH, H-4b);

1.04 (s, 9H, SiCH ₃ ).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 188.8 (CH = O), 161.9 (NHC = O), 150.4 (C2 ');

147.7 (C6 ') 145.7 (C2), 135.6 and 135.4 and 135.2 and 133.3 and 133.2 and

132.8 and 130.3 and 130.0 and 129.1 and 128.0 and 127.8 and 127.6 (all of Ph), 97.8 (C5 '), 63.2 (CH ₂ OSi), 60.8 (C3), 44.5 (C5), 34.4 (C4), 27.0 (SiC (CH ₃ ) ₃ ), 19.4 (SiC (CH ₃ )).

Preparation of (+) - (3 /?, 5S) -diphenyl-carbamic acid 2 '- acetylamino-9' - [4- (terf-butyl-diphenyl-silanyloxymethyl) -3-formyl-cyclopent-2-enyl] -9H -purin-6 '-yI ester (155d)

Compound (+) - 155d was obtained as a clear liquid according to the general experimental procedure (112 mg, 37% yield).

TLC: R _f = 0.41 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = +12.1 (c θ.75, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +13.7. H NMR (250 MHz, CDCI ₃ ): δ = 9.84 (s, IH, HC = O); 8.46 (s, IH, NH); 7.92

(s, 1Η, 8 ^' Η); 7.99 (s, 1Η, NH); 7.56-7.18 (m, 20Η, 4 x Ph); 6.76 (s, IH, H-

2); 5.74 (m, IH, H-3); 4.05 (dd, = 10.3, J ₂ = 6.0, IH, SiOCHa); 3.85 (dd, = 10.1, = 3.2, 1Η, SiOCHb); 3.25 (m, 1Η, Η-5); 2.85 (ddd, = 13.7, J ₂

= J ₃ = 8.5, IH, H-4a); 2:43 (s, 3H, CH ₃ CO); 2.06 (ddd, = 13.2, J ₂ = J ₃ =

5.8, 1Η, Η-4b); 1.00 (s, 9H, SiCH ₃ ).

¹³ C NMR (63 MΗz, CDCI ₃ ): δ = 188.9 (CΗ = O), 170.5 (CH ₃ C = O), 156.2 (C4 '),

154.6 and 152.1 and 150.3 (C2 '+ C6' + Ph ₂ NC = O), 149.4 (Cl), 146.7 (C2),

141.75 (C8 '), 141.64 and 135.5 and 135.3 and 133.1 and 132.9 and 129.75 and 129.772 and 129.1 and 127.65 and 127.60 and 126.9 (br) (all from

4xPh), 120.6 (C5 '), 63.2 (CH ₂ OSi), 58.2 (C3), 44.7 (C5), 35.3 (C4), 26.9

(SiC (CH ₃ ) ₃ ), 25.0 (CH ₃ C = O), 19.2 (SiC (CH ₃ ) ₃ ).

IR (ATR, cm ^"1 ): v = 3217 (w, NH), 3064 (w, NH), 2929 (w, CH), 2854 (w,

C-H), 1741 (s, NC = O); 1684 (s, CH = O), 1617 (s, C = C), 1586 (m), 1490 (m),

1450 (w), 1425 (w), 1372 (m), 1333 (m), 1281 (s), 1213 (s), 1185 (s), 1167 (s), 1108 (m), 1059 (m), 1001 (m), 931 (w), 907 (w), 822 (w), 785 (w), 741

(m), 700 (s), 664 (w).

MS (ESI, 70 eV): m / z (%) = 807 (11), 806 (29), 805 (51), 775 (10), 774

(27), 773 ([M + Na] ⁺ , 47), 679 (3), 594 (3), 562 (5), 519 (5), 443 (2), 413

(5), 412 (23), 411 (100), 369 (2), 196 (17), 168 (11).

HRMS (ESI) C ₄₃ H ₄₂ N ₆ NaO ₅ Si [M + Na] ⁺ : calcd 773.288, found 773.288.

General regulation for the reduction of aldehydes (95) and (155)

(+) - 95 (R = ThxMe ₂ Si) (-) - 113 (R = ThxMe ₂ Si)

(+) - 155 (R =.-BuPh ₂ Si) (-) - 159 (R =.-BuPh ₂ Si)

A mixture of MeOH (6 ml) and CH ₂ Cl ₂ (12 m!) Was added to NaBH ₄ (76 mg, 2 mmol, 10 equiv.) And the mixture was stirred for 3 min. stirred at RT before the mixture was cooled to -78 ° C (dry ice-acetone bath). A solution of (+) - 95 or (+) - 155 (200 μmol) in CH ₂ CI ₂ (2 ml) was added dropwise. After the reaction mixture had been stirred at -78 ° C. for 1 h, 5 ml of acetone were added and the mixture was slowly warmed to RT, with stirring at RT for a further 30 min. The reaction mixture was applied to a column loaded with silica gel and extracted with EtOAc. The solvent was then evaporated off, the allyl alcohol 113 or (-) - 159 being formed as the residue in a high degree of purity according to ^X H NMR and TLC. Preparation of (-) - (l 'Λ, 4' S) -l- {4 '- [Dimethyl- (l, l _/ 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent-2 '- enyl} -lH-pyrimidine-2,4-dione (113a)

Compound (-) - 113a was obtained as a clear liquid (59 mg, 78% yield) according to the general experimental procedure.

m.p. = 60-62 ° C (EtOAc / CyHex).

TLC: R _f = 0.17 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = -84.6 (c 0.33, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = -101.3.

* H NM (250 MHz, CDCI ₃ ): δ = 9.00 (bs, IH, NH); 7.34 (d, J = 8.0, 1Η, Η-6);

5.67 (dd, = 8.0, J ₂ = 2.2, H-5); 5.62 (ddd, = 8.5, J ₂ = J ₃ = 1.9, IH, Hl ');

5.52 (s, IH, H-2 ^' ); 4.26 (s, 2H, CH ₂ OH); 3.79 (dd, J _x = 10.5, J ₂ = 3.6, IH,

SiOCHa); 3.52 (dd, = 10.5, J ₂ = 6.1, .1Η, SiOCHb); 2.86 (m, 1Η, Η-4 ');

2.71 (ddd, = 13.5, J ₂ = J ₃ = 8.5, IH, H-5 ^' a); 1.59 (septet, J = 6.8, 2H, OH

+ Me ₂ CH); 1.39 (ddd, = 13.5, J ₂ = J ₃ = 6.9, 1Η, Η-5 'b); 0.85 (d, J = 6.8,

6H, (CH ₃ ) ₂ CH); 0.83 (s, 6H, C (CH _{3) 2);} 0.10 + 0.09 (2 xs, ^' 6Η, CH ₃ Si).

¹³ C NMR (63 MΗz, CDCI ₃ ): δ = 163.3 (C4), 152.7 (C3 ^' ), 151.0 (C2), 141.2

(C6), 124.7 (C2 '), 102.4 (C5), 64.1 (CΗ ₂ OSi), 60.5 (CH ₂ OH), 59.6 (Cl'),

46.9 (C4 ^' ), 34.1 (C5'), 34.0 (Me ₂ CH), 25.3 (Me ₂ CSi), 20.3 and 20.2

((CH ₃ ) ₂ CH), 18.5 and 18.4 ((CH ₃ ) ₂ CSi), -3.49 and -3.51 (CH ₃ Si).

IR (ATR, cm ^"1 ): v = 3406 (w, OH), 3178 (w, NH), 3043 (m, NH), 2951 (m,

C-H), 2862 (m, CH), 1753 (w), 1693 (s, C = O), 1697 (s, C = O), 1666 (s, C = N),

1651 (m, C = C), 1461 (s), 1416 (m), 1377 (m), 1275 (m), 1248 (s, C-O),

1174 (m), 1112 (m), 1060 (m), 1039 (m), 994 (m), 934 (w), 871 (m), 828

(s), 804 (m), 775 (s), 719 (m), 694 (m), 666 (m).

MS (EI, 70 eV): m / z (%): 333 (6), 295 [M-85] ⁺ (10), 278 (14), 277 (38), 247

(3), 199 (7), 183 (18), 169 (8), 129 (4), 117 (8), 105 (23), 91 (100), 77

(10), 75 (14).

HRMS (ESI) [M + Na] ⁺ Cι ₉ H ₃₂ N ₂ NaO ₄ Si: calcd 403.203, found: 403.204. Preparation of (+) - (l 'S, 4' /?) - l- {4 ^ Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyI] -3 '-hydroxymethyl-cyclopent-2' -enyl } -lf / - pyrimidine-2,4-dione (113a)

Compound (+) - 113a was obtained as a clear liquid (72 mg, 95% yield) according to the general experimental procedure.

[ä] _D ²⁰ = +61 (c 0.26, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +76, [ä] ₄₀₅ ²⁰ = +199, [ä] ₃₆₅ ²⁰ = +309, [ä] ₃₃₄ ²⁰ = + 509th

Preparation of (-) - (l 'Ä, 4' S) -5-fluoro-l- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent -2 '- enyI> -l // - pyπmidin-2,4-dione (113b)

The compound (-) - 113b was obtained as a colorless oil (48 mg, 99% yield) according to the general experimental procedure.

m.p. = 165-167 ° C (EtOAc / Hex).

TLC: R _f = 0.40 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = -77.0 (c 0.46, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = -95.3, [ä] ₄₀₅ ²⁰ = -252.8, [ä] ₃₆₅ ²⁰ =

-404.4, [ä] ₃₃₄ ²⁰ = - 702.2.

^X H NMR (250 MHz, CDCI ₃ ): δ = 9.92 (bs, IH, NH); 7.42 (d, J _{Η; F} = 5.9, IH, H-6); 5.62 (m, IH, Hl '); 5.53 (s, IH, H-2 '); 4.31 (d, J = 14.6, IH, CHaOH); 4.23 (d, J = 15.0, IH, CHbOH); 3.80 (dd, = 10.4, J ₂ = 3.4, IH, SiOCHa); 3.53 (dd, = 10.4, J ₂ = 5.2, 1Η, SiOCHb); 2.86 (m, 1Η, Η-4 '); 2.70 (ddd, = 13.6, J ₂ = J ₃ = 8.6, 1Η, Η-5 'a); 1.58 (septet, J = 6.8, IH, Me ₂ CH); 1.43 (ddd, = 13.7, J ₂ = J ₃ = 6.6, 1Η, Η-5 'b); 0.84 (d, J = 7.0, 6Η, (CH ₃ ) ₂ CH); 0.82 (s, 6H, C (CH _{3) 2);} 0.10 + 0.08 (2 xs, 6Η, CH ₃ Si).

¹³ C MMR (63 MΗz, CDCI ₃ ): δ = 157.1 (d, J _{C; F} = 26, C4), 153.2 (C3 ^' ), 149.8 (C2), 140.6 (d, J _C , _F = 236, C6 ), 125.3 (d, J _C , _F = 32, C5), 124.2 (C2 '), 63.7 (CΗ ₂ OSi), 60.4 (CH ₂ OH), 60.1 (Cl'), 46.8 (C4 ^' ), 34.0 ( Me ₂ CH), 33.7 (C5 ^' ), 25.3 (Me ₂ CSi), 20.3 and 20.1 ((CH ₃ ) ₂ CH), 18.41 and 18.36 ((CH ₃ ) ₂ CSi), -3.5 and -3.6 (CH ₃ Si). IR (ATR, cm ^"1 ): v - 3416 (w, OH), 3178 (w, NH), 3056 (w, NH), 2954 (m,

C-H), 2864 (m, CH), 1692 (s, C = O), 1659 (s, C = C), 1465 (m), 1389 (m),

1344 (w), 1273 (m), 1239 (s, C-O), 1151 (w), 1109 (m), 1088 (m), 1062

(m), 1036 (m), 994 (m), 938 (w), 885 (m), 830 (s), 779 (m), 707 (w).

MS (ESI, 70 eV): m / z (%): 835 [2M + K] ⁺ (4), 819 [2M + Na] ⁺ (4), 463 (25),

421 [M + Na] ⁺ (100), 399 [M + H] ⁺ (2), 286 (4), 269 (10).

HRMS (ESI) C ₁₉ H ₃ IFN ₂ NaO ₄ Si [M + Na] ⁺ : calcd. 421.194, found: 421.194.

Preparation of (+) - (! 'S, 4' R) -5-fluoro-l ~ (4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent -

2 "-enyl> -lH-pyrimidine-2> 4-dione (113b)

Compound (+) - 113b was obtained as a yellow liquid according to the general experimental procedure (85 mg, 93% yield).

[ä] _D ²⁰ = +71.1 (c 0.68, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = +88.3, [ä] ₄₀₅ ²⁰ = +234.6, [ä] ₃₃₄ ²⁰ = +649.1.

Preparation of (-) - (l 'R, 4' S) -l- {4 '- [Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3' -hydroxymethyl-cyclopent-2 '- enyl} -

5-methyl-li4 ^r -pyrimidine-2,4-dione (113c)

Compound (-) - 113c was obtained as a clear liquid (69 mg, 88% yield) according to the general experimental procedure.

m.p. = 108-109 ° C (EtOAc / CyHex).

TLC: R _f = 0.21 in EtOAc / CyHex = 4 + 1.

[ä] _D ²⁰ = -67.9 (c 0.50, CHCI3), [ä] ₅₄₆ ²⁰ = -83.6, [ä3 ₄ o ₅ ²⁰ = -223.8, [ä3 ₃₆₅ ²⁰ =

-357.8, [aJ33 = -622.7. ¹ H NMR (250 MHz, CDCI ₃ ): δ = 8.62 (bs, IH, NH); 7.05 (d, J = 1.2, 1Η, Η-6);

5.59 (dddd, = 7.8, J ₂ = 7.6, J ₃ = J ₄ = 2.1, IH, Hl '); 5.53 (s, IH, H-2 ');

4.27 (d, J = 5.8, 2H, CH ₂ OH); 3.77 (dd, 3 ₁ = 10.3, J ₂ = 3.7, IH, SiOCHa); 3:52

(dd, = 10.3, J ₂ = 6.3, 1Η, SiOCHb); 2.87 (m, 1Η, Η-4 '); 2.65 (ddd, = 13.3, J ₂ = J ₃ = 8.4, IH, H-5 'a); 1.88 (d, J = 1.2, 3H, CH _3); 1.67 (bs, 1Η, OΗ);

1.60 (septet, J = 6.9, 1Η, Me ₂ CH); 1.35 (ddd, = 13.6, J ₂ = J ₃ = 7.7, 1Η, Η-

5 'b); 0.86 (d, J = 6.9, 6Η, (CH ₃ ) ₂ CH); 0.83 (s, 6H, C (CH _{3) 2);} 0.11 +

0.10 (2 xs, 6Η, CH ₃ Si).

¹³ C NMR (63 MHz, CDCI ₃ ): δ = 163.8 (C4), 152.3 (C3 '), 150.1 (C2), 136.6

(C6), 125.2 (C2 '), 110.1 (C5), 64.1 (CH ₂ OSi), 60.6 (CH ₂ OH), 59.4 (Cl'),

46.7 (C4 '), 34.2 (C5'), 34.1 (Me ₂ CH), 25.2 (MezCSi), 20.2 ((CH ₃ ) ₂ CH), 18.5

((CH ₃ ) ₂ CSi), 12.4 (CH ₃ ), -3.5 and -3.6 (CH ₃ Si).

IR (ATR, cm ^"1 ): v = 3404 (w, OH), 3173 (w, N-H), 3042 (w, NH), 2953 (m,

C-H), 2863 (m, CH), 1681 (s, C = O), 1465 (m), 1387 (m), 1378 (m), 1359

(w), 1276 (m), 1249 (s), 1222 (m, C-O), 1149 (w), 1111 (m), 1088 (m),

1060 (m), 1044 (m), 1009 (m), 993 (m), 937 (w), 908 (w), 874 (m), 829 (s),

777 (m), 763 (m).

MS (EI, 70 eV): m / z (%): 380 (6), 310 (4), 293 (7), 290 (12), 276 (10), 217

(11), 216 (87), 186 (9), 183 (34), 178 (18), 168 (21), 112 (25), 105 (100),

91 (28), 89 (15), 77 (29), 75 (50), 73 (30).

HRMS (ESI) [M + Na] ⁺ C ₂₀ H ₃₄ N ₂ NaO ₄ Si: calcd. 417.2186, found: 417.219.

Preparation of (+) - (l 'S, 4' R) -l- {4 '- [Dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent-2 '-enyI } -5- methyl-lH-pyrimidine-2,4-dione (113c)

Compound (+) - 113c was obtained as a clear liquid (79 mg, 99% yield) according to the general experimental procedure.

Darstellung von (+)-(l 'S, 4 'Λ)-/V-(l-{4 '-[Dϊmethyl-(l,l,2-trimethyI- propyI)-silanyloxymethyl3-3-hydroxymethyI-cyclopent-[ä3 _D ²⁰ = +70 (c 0.16, CHCI ₃ ), [ä ₅₄ 6 ²⁰ = +87, [ä3 ₄₀₅ ²⁰ = +223, [a ₃₆ 5 ⁰ =

Representation of (+) - (l 'S, 4' Λ) - / V- (l- {4 '- [Dϊmethyl- (l, l, 2-trimethyI-propyI) -silanyloxymethyl3-3-hydroxymethyI-cyclopent-

2 '-enyI} -2-oxo-l, 2-dihydro-pyrimidin-4-yl) -benzamide (113d-l)

Compound (+) - 113d-1 was obtained as a yellow oil according to the general experimental procedure (97 mg, 99% yield).

TLC: R _f = 0.55 in EtOAc / MeOH = 4 + 1.

[ä3 _D ²⁰ = +65 (c θ.12, CHCI ₃ ).

^X NMR (250 MHz, CDCI ₃ ): δ = 7.89 (d, J = 6.3, IH, H-6); 7.79 (d, J = 6.0,

IH, H-5); 7.62-7.34 (m, 5H, Ph); 5.77 (m, IH, H-1 '); 5.60 (s, IH, H-2 ');

4.30 (s, 2H, CH ₂ OH); 3.78 (dd, = 8.8, J ₂ = 2.8, IH, SiOCHa); 3.51 (dd, =

8.8, J ₂ = 5.0, 1Η, SiOCHb); 2.90 (m, 1Η, Η-4 ^' ); 2.86 (ddd, = 10.5, J ₂ = J ₃ =

7.0, 1Η, Η-5 'a); 1.60 (septet, J = 6.8, IH, Me ₂ CH); 1.40 (ddd, = 9.3, J ₂ = J ₃

= 5.3, 1Η, Η-5 'b); 0.86 (d, J = 5.8, 6H, (CH ₃ ) ₂ CH); 0.84 (s, 6H, C (CH _{3) 2);}

0.11 + 0.09 (2 xs, 6Η, CH ₃ Si);

¹³ C NMR (63 MΗz, CDCI ₃ ): δ = 161.9 (C4), 153.4 (C3 '), 145.7 (C6), 133.1 and 129.0 and 128.5 and 127.6 (all of Ph), 124.7 (C2'), 85.1 ( C5), 64.4

(CΗ ₂ OSi), 61.4 (CH ₂ OH), 60.6 (Cl '), 47.2 (C4'), 35.1 (C5 '), 34.0 (Me ₂ CH),

25.3 (Me ₂ CSi), 20.29 and 20.19 ((CH ₃ ) ₂ CH), 18.48 and 18.44 ((CH ₃ ) ₂ CSi), -

3.5 (CH ₃ Si);

IR (ATR, cm ^"1 ): = 3295 (bw, OH), 3062 (w, NH), 2954 (m, CH), 2863 (m,

C-H), 1693 (m, C = O), 1649 (s, C = N), 1643 (s, C = C), 1620 (s, C = C), 1556

(m), 1485 (s), 1380 (s), 1300 (m), 1249 (s, C-O), 1190 (m), 1176 (m), 1109

(m), 1092 (m), 1028 (m), 1002 (m), 930 (w), 873 (w), 830 (m), 802 (m),

778 (m), 704 (m), 665 (m);

M (EI, 70 eV): m / z (%): 407 (6), 333 (3), 310 (10), 309 (57), 307 (18), 289

(5), 261 (13), 217 (7), 215 (9), 201 (10), 184 (13), 183 (100), 181 (16), 174

(10), 153 (4), 127 (28), 105 (36), 91 (91), 89 (25), 75 (61), 73 (33);

HRMS (EI) [M + Na] ⁺ C ₂₆ H ₃₇ N ₃ NaO ₄ Si: calcd 506.245, found: 506.245.

Representation of (-) - (l 'Λ, 4' S) - / V- (l- {4 '- [dimethyl- (l, l, 2-trimethyl- propyl) -silanyloxymethyl3-3-hydroxymethyl-cyclopent-2 '-enyl> -2-oxo-l, 2-dihydro-pyrimϊdϊn-4-yl) -benzamide (113d-l)

The compound (-) - 113d-l was obtained according to the general experimental procedure as a mixture of the protected and free alcohol, which was used directly in the following reaction to remove the protective group.

Preparation of (+) - (l 'R, 4' S) -4-amino-l- {4 '- [dimethyl- (l, l, 2-tπmethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent- 2 '- enyl> -lH-pyrimidin-2-one (113d)

A 2 M solution of ammonia in MeOH (2 ml, 4 mmol, 40 equiv.) Was added to a solution of (+) - 113d-l (48 mg, 100 μmol) at RT under an argon atmosphere and the reaction mixture stirred for 16 h. The solvent and ammonia were evaporated and the residue was purified by flash chromatography (EtOAc / CyHex = 4 + 1? EtOAc / MeOH = 4 + 1). Compound (+) - 113d was obtained as a yellow oil (36 mg, 95% yield).

TLC: R _f = 0.27 in EtOAc / MeOH = 4 + 1.

[ä3 _D ²⁰ = +91.6 (c θ.31, MeOH), [ä3 ₅₄₆ ²⁰ = +112.1, [ä3 ₄₀₅ ²⁰ = +298.6,

[ä3 ₃₆₅ ²⁰ = +479.8.

^X H NMR (250 MHz, ⁴ -MeOH): δ = 7.49 (d, J = 6.0, IH, H-6); 5.79 (d, J =

6.0, IH, H-5); 5:50 (bs, 2H, NH _2); 4.25 (d, 3 = 13.0, -lΗ, ^' CHaOH); 4.10 (d, 3

= 13.0, IH, CHbOH); 3.71 (dd, = 8.8, 3 ₂ = 3.5, IH, SiOCHa); 3.51 (m, 1Η,

SiOCHb); 3.29 (s, 1Η, Η-2 '); 3.23 (m, IH, H-1 '); 2.81 (m, IH, H-4 '); 2.64

(ddd, = 11.5, 3 ₂ = 3 ₃ = 7.3, IH, H-5 'a); 1.54 (septet, J = 5.5, IH, Me ₂ CH);

1.46 (ddd, = 11.5, J ₂ = J ₃ = 5.5, 1Η, Η-5 ^' b); 0.80 (d, J = 5.5, 6H,

(CH ₃ ) ₂ CH); 0.78 (s, 6H, C (CH _{3) 2);} 0.03 + 0.01 (2 xs, 6Η, CH ₃ Si).

¹³ C MMR (63 MΗz, d ⁴ -MeOΗ): δ = 167.3 (C4), 158.9 (C2), 154.1 (C3 '), 143.8

(C6), 124.9 (C2 '), 96.0 (C5), 64.4 (CH ₂ OSi), 62.2 (Cl'), 60.9 (CH ₂ OH), 48.0

(C4 '), 35.9 (C5'), 35.4 (Me ₂ CH), 26.3 (Me ₂ CSi), 21.0 and 20.8 ((CH ₃ ) ₂ CH),

19.05 and 18.98 ((CH ₃ ) ₂ CSi), -3.3 (CH ₃ Si).

IR (ATR, cm ^"1 ): = 3330 (bm, OH), 3199 (m, NH), 2954 (m, CH), 2863 (m,

CH), 1714 (w, C = O), 1640 (s, C = N), 1613 (s, C = C), 1578 (m, C = C), 1524 (m), 1487 (m), 1397 (m), 1357 (w), 1281 (m), 1250 (m, CO), 1217 (w),

1185 (m), 1112 (m), 1085 (m), 1060 (m), 996 (m), 965 (w), 931 (w), 873

(w), 830 (m), 778 (m), 709 (m).

MS (ESI, 70 eV): m / z (%): 797 (3), 784 (4), 783 (14), 782 (18), 781 (36),

761 (3), 760 (7), 759 (10), 667 (2), 529 (3), 450 (3), 434 (6), 424 (5), 418

(4), 404 (7), 403 (27), 402 [M + Na] ⁺ (100), 374 (2), 342 (2), 325 (2), 291

(2), 277 (2), 166 (4), 134 (39), 127 (7), 112 (43).

HRMS (ESI) C ₁₉ H ₃₃ N ₃ O ₃ NaSi [M + Na] ⁺ : calcd 402.219, found 402.218.

Preparation of (-) - (l 'S, 4' R) ~ 4-amino-l- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroxymethyl-cyclopent- 2 '- enyl> -lJ ¥ -pyrimϊdin-2 ~ one (113d)

The compound (-) - 113d was obtained as a clear liquid (59 mg, 85% yield) according to the experimental procedure, the crude product of the reduction reaction being used immediately, as described above. m.p. = 189-193 ° C (dec, EtOAc / Hex).

[ä3 _D ²⁰ = -97.9 (c 0.33, MeOH), [ä3 ₅ 46 ⁰ = -120.6, [ä3 ₄ o ₅ ²⁰ = -325.6, [ä3 ₃₆₅ ²⁰

= -524.1, [ä3 ₃₃₄ ²⁰ = -912.5.

Preparation of (-) - (i 'R, 4' S) -2-amino-9- {4 '- [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl3-3' -hydroexymethyl-cyclopent- 2 '- enyl> -l, 9-dihydro-purin-6-one (113e)

(+) - 95e (-) - 113e The reduction reaction was carried out according to the general experimental procedure, except that the solvent did not evaporate. the reaction mixture was immediately stirred with 2 M ammonia in MeOH (5 ml) at RT for 16 h. The solvent was then evaporated and the residue was purified by flash chromatography (EtOAc / MeOH = 4 + 1), leaving 30 mg of the compound (-) - 113e as a clear liquid (71% yield).

m.p. = 230 ° C (dec, EtOAc / CyHex).

TLC: R _f = 0.58 in EtOAc / MeOH = 4 + 1.

[ä3o ²⁰ = -55.4 (c 0.31, MeOH), [a3 ₅₄₆ ²⁰ = -66.7, [ä3 ₄₀₅ ²⁰ = -148.2, [ä3 ₃₆₅ ²⁰

= -205.2. ^l NMR (250 MHz, d ⁴ -MeOH): δ = 7.66 (s, IH, H-8); 5.80 (s, IH, H-2 ');

5.42 (m, IH, H-1 '); 4.37 (d, 3 = 15.0, IH, CHaOH); 4.21 (d, 3 = 15.0, IH,

CHbOH); 3.77 (dd, 3 _X = 10.3, J ₂ = 4.9, IH, SiOCHa); 3.66 (dd, = 10.2, 3 =

4.4, 1Η, SiOCHb); 2.95 (m, 1Η, Η-4 '); 2.76 (ddd, J _t = 13.7, 3 ₂ = 3 ₃ = 8.5, 1Η,

Η-5 'a); 1.83 (ddd, = 13.6, 3 ₂ = 3 ₂ = 5.9, IH, H-5 'b); 1.60 (septet, J = 6.9,

IH, Me ₂ CH); 0.87 (d, J = 6.9, 6Η, (CH ₃ ) ₂ CH); 0.84 (s, 6H, C (CH _{3) 2);} 0.08 and

0.07 (2 xs, 6Η, CH ₃ Si).

¹³ C NMR (63 MΗz, ⁴ -MeOΗ): δ = 159.4 (C6), 155.2 (C2), 153.8 (C4), 152.7

(C3 '), 137.3 (C8), 128.8 (C5), 124.4 (C2 ^' ), 64.8 (CH ₂ OSi), 60.9 (CH ₂ OH),

59.3 (Cl ^' ), 48.6 (C4 ^' ), 36.7 (C5 '), 35.5 (Me ₂ CH), 26.3 (Me ₂ CSi), 20.93 and

20.84 ((CH ₃ ) ₂ CH), 19.00 and 18.96 ((CH ₃ ) ₂ CSi), -3.4 ((CH ₃ ) ₂ Si).

ΪR (ATR, cm ^"1 ): v = 3364 (m, OH), 3191 (m, NH), 2954 (m, CH), 2865

(m, C-H), 1686 (s, C = O). 1638 (s, C = N), 1608 (m, C = C), 1566 (m), 1534

(w), 1469 (w), 1407 (w), 1375 (m), 1314 (m), 1251 (m, C-O), 1223 (w),

1171 (m), 1083 (m), 830 (m), 777 (m), 696 (m).

MS (ESI, 70 eV): m / z (%): 883 (4), 864 (5), 863 (14), 862 (31), 861

[2M + Na] ⁺ (55), 484 (3), 474 (6), 464 (4), 445 (2), 444 (9), 443 (29), 442

[M + Na] ⁺ (100), 174 (8). HRMS (ESI) C ₂ oH ₃₃ N ₅ NaO ₃ Si [M + Na] ⁺ : calcd 442.225, found 442.225.

Preparation of (+) - (l ^' S, 4 ^' Λ) -2-amino-9- {4 ^' - [dimethyl- (l, l, 2-trimethyl-propyl) -silanyloxymethyl] -3 ^' -hydroxymethyl-cyclopent -2'- enyl} -l, 9-dihydro-purin-6-one (113e)

Compound 113e was made according to. the general test instructions obtained as a clear liquid (32 mg, 76% yield).

[ä3 _D ² ° = +68.1 (c 0.42, MeOH).

Preparation of (-) - (l ^'/ ?, ^4' S) -5-fluoro-l- [4 ^'- (£ he £ -butyl-diphenyl-silanyloxymethyl) ^-3' -hydroxymethyl-cyclopent-2 ^'-enyl3 -lH- pyrimidϊn-2,4-dione (159a)

Compound (-) - 159a was obtained as a colorless oil (25 mg, 99% yield) according to the general experimental procedure.

TLC: R _f = 0.43 in EtOAc / CyHex = 4 + 1.

[ä3 _D ²⁰ = -42.1 (c 0.44, CHCI ₃ ), [a s46 ²⁰ = -51.5, [ä3 ₄₀₅ ²⁰ = -142.1, [ä3 ₃ 6 ₅ ² ° =

-234.6.

¹ H NMR (250 MHz, CDCI ₃ ): δ = 9.20 (bs, IH, NH); 7.64-7.58 (m, 4Η, Ph); 7.46-7.35 (m, 6H, Ph); 7.31 (d, J _H , _F = 5.9, IH, H-6); 5.56 (m, 2H, Hl ^' + H-2'); 4.35 (d, J = 14.7, IH, CHaOH); 4.25 (d, J = 14.8, IH, CHbOH); 3.73 (dd, = 10.5, J ₂ = 4.4, IH, SiOCHa); 3.64 (dd, 3 _t = 10.5, J ₂ = 5.9, 1Η, SiOCHb); 2.88 (m, 1Η, Η-4 ^' ); 2.63 (ddd, = 14.0, 3 ₂ = 3 ₃ = 8.7, 1Η, Η-5 ^' a); 1.37 (ddd, = 14.0, = 3 ₃ = 7.3, IH, H-5 ^' b); 1:06 (s, 9H, (CH ₃₎ CSi). ¹³ C MMR (63 MΗz, CDCI ₃ ): δ = 153.6 (C3 ^' ), 149.5 (C2), 135.54 and 135.48 and 132.6 and 130.11 and 130.08 and 128.0 (all from Ph), 125.0 (d, J _{C / F} = 33, C6), 123.9 (C2 ^' ), 65.1 (CΗ ₂ OSi), 60.7 (CH ₂ OH), 60.3 (Cl ^' ), 46.8 (C4 '), 34.0 (C5 ^' ), 26.9 (SiC (CH ₃ ) ₃ ), 19.2 (SiC (CH ₃ ) ₃ ).

IR (ATR, cm ^"1 ): = 3399 (w, OH), 3176 (w, NH), 3065 (m, NH), 2927 (m, C-H), 2890 (w, CH), 2854 (m , CH), 1696 (s, C = O), 1659 (s, C = N), 1469 (m), 1425 (m), 1388 (m), 1344 (w), 1273 (m), 1239 (s), 1187 (w), 1152 (w),

1109 (s), 1061 (m), 995 (w), 936 (w), 888 (w), 821 (m), 784 (m), 741 (m),

702 (s).

MS (EI, 70 eV): m / z (%): 439 (2), 438 (5), 437 [M-57 (Bu)] ⁺ (14), 359 (8),

329 (3), 311 (10), 307 (17), 277 (3), 251 (11), 230 (7), 229 (41), 201 (6),

200 (18), 199 (100), 197 (9), 183 (6), 181 (9), 169 (6), 167 (6), 139 (11),

135 (12), 105 (8), 91 (27), 77 (8).

HRMS (EI) C ₂₃ H ₂₂ FN ₂ O ₄ Si [M-57 (Bu)] ⁺ : calcd 437.133, found: 437.133.

Representation of (+) - (! '/?, 4 ^' S) -5-bromo-l- [4 '- (ferf-butyl-diphenyI- sHanylo ^ methyI) -3' -hydroxymethy! -Cy opent-2 ' -enyl] -l / - pyrϊmidϊn-2,4-dione (159b)

Compound (-) - 159b was prepared according to the. general test instructions obtained as a colorless oil (56 mg, 99% yield).

TLC: R _f = 0.39 in EtOAc / CyHex = 4 + 1.

[ä3 _D ²⁰ = +18.5 (c 0.52, CHCI ₃ ), [ä3 ₅₄₆ ²⁰ = +21.7, [ä] ₃₃₄ ²⁰ = -37.5.

^X H NMR (250 MHz, CDCI ₃ ): δ = 9.74 (s, IH, NH); 7.64 - .7.58 (m, 4Η, Ph); 7.52 (s, IH, H-6); 7.43-7.34 (m, 6H, Ph); 5.58 (d, 3-1.7, IH, H-2 ^' ); 5.55 (dd, = J ₂ = 8.2, IH, Hl ^' ); 4.37 (d, 3 = 14.6, IH, Cr / aOH); 4.27 (d, 3 = 14.7, IH, CHbOH); 3.71 (dd, =. 10.5, 3 ₂ = 4.6, IH, SiOCHa); 3.63 (dd, J ₁ = 10.5, 3 ₂ = 6.0, 1Η, SiOCHb); 2.87 (m, 2Η, H-4 '+ OH); 2.61 (ddd, = 13.7, 3 ₂ = 3 ₃ = 8.2, IH, H-5 'a); 1.33 (ddd, = 13.6, J ₂ = J ₃ = 7.4, IH, H-5 ^' b); 1:06 (s, 9H, (CH _{3) 3} CSi).

¹³ C NMR (63 MΗz, CDCI3): δ = 159.2 (C4), 153.6 (C3 ') _; 150.4 (C2), 140.3 (C6), 135.50 and 135.48 and 132.61 and 132.58 and 130.07 and 130.03 and 127.9 (all of Ph), 123.7 (C2 '), 96.7 (C5), 65.0 (CΗ ₂ OSi), 61.0 (CH ₂ OH), 60.6 (Cl '), 46.8 (C4'), 34.5 (C5 '), 26.9 ((CH ₃ ) ₃ CSi), 19.2 ((CH ₃ ) ₃ CSi). IR (ATR, cm ^{* 1} ): v = 3425 (w, OH), 3173 (w, NH), 3065 (m, NH), 3044 (w), 2927 (m, CH), 2854 (m, CH) , 1691 (s, C = O), 1683 (s, C = O), 1615 (m, C = C), 1587 (w), 1469 (w), 1444 (m), 1426 (m), 1388 ( w), 1375 (w), 1360 (w), 1331 (w), 1274 (m), 1238 (m), 1186 (w), 1150 (w), 1110 (s), 1086 (m),

1064 (m), 1036 (m), 1005 (w), 996 (w), 937 (w), 919 (w), 839 (w), 822 (m),

786 (w), 741 (m), 702 (s), 650 (w), 627 (w), 616 (m).

MS (ESI, 70 eV): m / z (%): 1225 (2), 1035 (5), 957 (8), 663 (2), 599 (3), 597

(4), 586 (2), 585 (9), 584 (29), 583 (100), 582 (30), 581 (92), 580 (14), 579

(46), 578 (12), 577 [M + Na] ⁺ (42), 533 (4), 517 (4), 511 (6), 504 (3), 503

(9), 502 (23), 501 (67), 463 (2), 421 (7), 389 (2), 388 (5), 387 (15), 365

(2), 287 (3), 233 (2), 169 (2), 147 (6).

HRMS (ESI) C ₂₇ H ₃ ιBrN ₂ NaO ₄ Si [M + Na] ⁺ : calcd 577.113, found: 577.114.

Preparation of (-) - (l 'R, 4 S) -l ¥ - [l- [4' - (rert-butyl-diphenyl-siIanyloxymethyl) -3 '-hydroxymethyl-cyclopent-2' -enyI] -2 -oxo-l, 2- dϊhydro-pyrimidin-4-yl} -benzamide (159c-l)

The compound (-) - 159c-1 was obtained as a light yellow liquid according to the general experimental procedure (23 mg, 79% yield).

m.p. = 190-193 ° C (EtOAc / CyHex).

TLC: R _f = 0.54 in EtOAc / MeOH = 4 + 1.

[ä] _D ²⁰ = -25.4 (c 1.05, CHCI ₃ ), [ä] ₅₄₆ ²⁰ = -33.2, [ä] ₄₀₅ ²⁰ = -153.2.

* H NMR (250 MHz, CDCI ₃ ): δ = 7.90 (d, 3 = 7.5, 2H, H-6 _. + H-Ph); 7.73 (d. 3

= 7.4, IH, H-5); 7.59-7.34 (m, 14H, Ph); 5.71 (m, IH, H-1 '); 5.63 (s, IH, H-

2 '); 4.39 (d, 3 = 15.5, IH, CH ₂ OH); 4.29 (d, 3 = 15.5, IH, CH ₂ OH); 3.73 (dd, = 10.6, J ₂ = 4.0, IH, SiOCH ₂ ); 3.58 (dd, = 10.6, 3 ₂ = 6.3, IH, SiOCH ₂ );

2.92 (m, 1Η, Η-4 ^' ); 2.78 (ddd, 3 ₁ = 13.6, 3 ₂ = 3 ₃ = 8.1, 1Η, Η-5 'a); 1.34 (m,

IH, H-5 ^' b); 1:05 (s, 9H, Si (CH _{3) 3).}

¹³ C NMR (63 MΗz, CDCI ₃ ): δ = 161.8 (C4), 158.9 (PhC = O), 153.4 (C3 ^' ),

145.5 (C6), 135.52 and 135.46 and 133.1 and 132.7 and 132.6 and 130.09 and 130.05 and 129.0 and 127.9 and 127.6 (all of Ph), 124.4 (C2 '), 65.4

(CΗ ₂ OSi), 61.5 (Cl '), 60.8 (CH ₂ OH), 47.0 (C4'), 35.0 (C5 ^' ), 26.9

(SiC (CH ₃ ) ₃ ), 19.2 (SiC (CH ₃ ) ₃ ). IR (ATR, cm ^"1 ): v = 3309 (bw, OH), 3067 (w, NH), 2955 (m, CH), 2928 (m, CH), 2855 (m, CH), 1696 (m, C = O), 1643 (s, C = N), 1620 (s, C = C), 1556 (m), 1485 (s), 1445 (m), 1426 (m), 1382 (s), 1306 ( s), 1253 (s), 1189 (w), 1110 (s), 1027 (w), 1003 (m), 933 (w), 893 (w), 822 (m), 788 (m), 741 ( m), 701 (s), 677 (m), 613 (m).

Preparation of (-) - (l 'Ä, 4' S) - 4-Amino-l- [4 '- (Er-butyl-dϊphenyl-silanyloxymethyl) -3' -hydroxymethyl-cyclopent-2 '-enyI] - lH-pyrimidin-2-one (159c)

Compound (-) - 159c was obtained as a clear liquid (16 mg, 96% yield) according to the general test procedure for deprotection.

m.p. = 198-201 ° C (dec, EtOAc / CyHex).

TLC: R _f = 0.33 in EtOAc / MeOH = 4 + 1.

[ä] _D ²⁰ = -54.5 (c 0.31, MeOH), [ä] ₅₄₆ ²⁰ = -67.6, [ä] ₄₀₅ ²⁰ = -187.3, [ä] ₃₆₅ ²⁰

= -310.1.

¹ H NMR (250 MHz, CDCI ₃ ): δ - 7.60-7.56 (m, 4H, Ph-H); 7.42-7.33 (m, 7H,

H-6 + Ph-H); 5.61-5.48 (m, ^" 3H, Hl '+ H-2' + H-5); 4.34 (d, J = 14.6, IH,

CHaOH); 4.24 (d, J = 14.6, IH, CHbOH); 3.74-3.52 (m, 4H, SiOCH ₂ + NH ₂ );

2.84 (m, 1Η, Η-4 '); 2.64 (m, 1Η, Η-5 'a); 1.28 (m, IH, H-5 'b); 1.03 (s, 9H,

Si (CH ₃ ) ₃ ).

¹³ C HMR (63 MΗz, CDC1 ₃ ): δ = 153.4 (C3 '), 142.8 (C6), 135.53 and 135.48 and 132.9 and 132.6 and 130.06 and 129.94 and 127.89 and 127.83 (all of

Ph), 125.1 (C2 '), 94.6 (C5), 65.5 (CΗ ₂ OSi), 61.7 (Cl'), 60.8 (CH ₂ OH), 46.9

(C4 ^' ), 34.8 (C5 ^' ), 26.9 (SiC (CH ₃ ) ₃ ). 19.2 (SiC (CH ₃ ) ₃ ).

ΪR (ATR, cm ^"1 ): v = 3338 (bs, OH + NH), 2953 (m, CH), 2928 (m, CH),

2854 (w / C-H), 1714 (w, C = O), 1640 (s, C = N), 1527 (m), 1486 (s), 1425

(m), 1398 (m), 1358 (m), 1280 (m), 1218 (w), 1184 (w), 1110 (m), 1083

(m), 1061 (m), 1005 (m), 996 (m), 821 (m), 778 (s), 738 (s). MS (ESI, 70 eV): m / z (%): 1166 (3), 973 [2M + Na] ⁺ (14), 951 [2M + H] ⁺ (3), 606 (6), 546 (2nd ), 530 (4), 520 (4), 514 [M + K] ⁺ (3), 500 (10), 499 (31), 498 [M + Na] ⁺ (100), 485 (8), 387 (8), 134 (25), 112 (27). HRMS (ESI) [M + Na] ⁺ C ₂₇ H ₃₃ N ₃ NaO _.3 Si: calcd 498.219, found: 498.219.

Preparation of (-) - (1 'R, 4' S) - 2-amino-9- [4 '- (£ er-butyl-diphenylsilanyloxymethyl) -3' -hydroxymethyl-cyclopent-2 '-enyl] -l, 9-dihydro-purin-6-one (159d)

Compound (-) - 159d was obtained as a clear liquid (26 mg, 99% yield) according to the general test procedure for the one-pot reaction with ThxMe ₂ Si-guanine.

m.p. > 260 ° C (dec, EtOAc / CyHex).

TLC: R _f = 0.50 in EtOAc / MeOH = 4 + 1.

[ä] _D ²⁰ = -34.8 (c θ.72, MeOH), [ä] ₅₄₆ ²⁰ = -40.6.

^X H NMR (250 MHz, d ⁴ -MeOH): δ = 7.60-7.32 (m, 11H, Ph + H-8); 5.84 (s, IH,

H-2 '); 5.39 (m, IH, Hl ^' ); 4.37 (d, J = 15.6, IH, CHaOH); 4.19 (d, J = 15.7,

IH, CHbOH); 3.79 (dd, = 10.3, 3 ₂ = 4.9, IH, SiOCHa); 3.69 (dd, 3 _X = 10.3,

J ₂ = 5.7, 1Η, SiOCHb); 2.99 (m, 1Η, Η-4 '); 2.72 (ddd, = 13.7, J ₂ = J ₃ = 8.5,

1Η, Η-5 'a); 1.81 (ddd, = 13.3, J ₂ = J ₂ = 6.2, IH, H-5 'b); 1.02 (s, 9H,

Si (CH ₃ ) ₃ ).

¹³ C NMR (63 MΗz, d ⁴ -MeOΗ): = 155.2 and 153.7 and 152.7 (C2 + C4 + C6),

152.0 (C3 '), 137.1 (C8), 136.68 and 136.64 and 134.50 and 134.42 and

131.00 and 130.96 (all of Ph), 124.4 (C2 '), 117.9 (C5), 66.2 (CH ₂ OSi), 61.0

(CH ₂ OH), 59.9 (Cl ^' ), 48.5 (C4'), 36.7 (C5 ^' ), 27.4 (SiC (CH ₃ ) ₃ ), 20.1

(SiC (CH ₃ ) ₃ ).

IR (ATR, cm ^"1 ): v = 3350 (m, OH), 3317 and 3191 (m, NH), 2934 (m, CH),

2891 (w, C-H), 2855 (m, C-H), 1683 (s, C = O), 1603 (m, C = C), 1531 (m),

1473 (w), 1370 (m), 1223 (w), 1172 (w), 1108 (m), 1072 (m), 822 (m), 780

(m), 739 (m), 701 (s), 631 (m). ^'

MS (ESI, 70 eV): m / z (%): 747 (12), 725 (7), 389 (10), 339 (100), 279 (4),

247 (7). (3 /? S, 5SK) -3- (5 ^' -Brom-2', 4'-dioxo-3 ^' , 4 ^' -dihydro-2H-pyrimidin-l yl) -5-hydroxymethyl-cyclopent-l-encarbaldehyde (rac-x2).

A solution of rec-xl (650 mg, 1.83 mmol) and PPTS (138 mg, 0.55 mol) in wet acetone (30 ml) was heated to reflux for 3 h. The solvent was then removed in vacuo, the reaction mixture was taken up in CH ₂ Cl ₂ and silica (3 g) was added. The solvent was again removed in vacuo and the residue was subjected to flash chromatography

(EtOAc). Rac-x2 was obtained as a white solid (510 mg,

88%).

TLC: R _f = 0.42 in EtOAc;

^X H-NMR (DMSO): δ = 9.83 (s, IH, HC = O), 8.07 (s, IH, H _Nb ), 6.91 (m, IH, H-

2), 5.62 (m, IH, H-3), 4.85 (dd, IH, HIGH _a ), 3.78 (dd, IH, HOCÜ), 3.05 (m,

IH, H-5), 2.65 (m, IH, H-4 _a ), 1.73 (m, IH, H-4 _b )

(3 ^ S, 5S ^) - 3- (5 ^" -S3rom-2% 4 ^' -diθ2co-3 ^' , 4 -dihydro-2H-pyrimidin-l ^' - ^' yl) -5- (e an lo v ~ ^m ε * "yl) -cyclopent-1-encarbaldehyde (rac-x3).

rac-x2 (510 mg, 1.62 mmol) wurde in trockenem DMF (10 ml) unter Argon vorgelegt und bei RT mit NaH versetzt (71 mg, 1.78 mmol; 60 % Suspension in Hexan). Nachdem 1 h bei RT gerührt wurde, wurde das Reaktionsgemisch mit Geranylbromid (1.06 g, 4.86 mmol) versetzt und weitere 16 h bei RT gerührt. Es wurde H₂O zugegeben (40 ml) und mit EtOAc extrahiert (5 x 50 ml). Die vereinigten organischen Phasen wurden mit NaCI (5 x 50 ml) gewaschen und über MgSO4 getrocknet. Das Lösungsmittel wurde im Vakuum entfernt und der Rückstand einer Flashchromatographie unterworfen. rac-x3 (433 mg, 59%) wurde als dunkel-gelbes Öl erhalten. DC: R_f= 0.14 in CyHex/EtOAc =2 + 1;

rac-x2 (510 mg, 1.62 mmol) was placed in dry DMF (10 ml) under argon and NaH was added at RT (71 mg, 1.78 mmol; 60% suspension in hexane). After stirring at RT for 1 h, the reaction mixture was mixed with geranyl bromide (1.06 g, 4.86 mmol) and stirred at RT for a further 16 h. H ₂ O was added (40 ml) and extracted with EtOAc (5 x 50 ml). The combined organic phases were washed with NaCl (5 x 50 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was subjected to flash chromatography. rac-x3 (433 mg, 59%) was obtained as a dark yellow oil. TLC: R _f = 0.14 in CyHex / EtOAc = 2 + 1;

^X H-MR (250 MHz, CDCI ₃ ,): δ = 9.88 (s, IH, HC = O), 7.83 (s, IH, H _Nb ), 6.69 (m, IH, H-2), 5.88 (m, IH, H-3), 5.20 (t, IH, H _Ger ), 5.02 (t, IH, H _Ger ), 4.56 (d, IH, H _Ger ), 4.08 (dd, IH, _G erOCH _a ) , 3.64 (dd, IH, _Ge rOCH _b ), 3.20 (m, IH, H-5), 2.85 (m, IH, H-4 _a ), 2.15-1.90 (m, 5H, H _Ger and H-4 _b ), 1.80-1.55 (m, 9H, H _Ger )

(l ^' ? S, 4' S /?) - 5-bromo-l- [4 '- (geranyloxy-methyl) -3' -hydroxynethyl-cyclopent-2 '-enyl] -lH-pyrimidine-2,4- dion (rac-x4) (AL-451)

NaBH ₄ (226 mg, 5.97 mmol) was dissolved in a MeOH / CH ₂ Cl ₂ mixture (12 ml + 24 ml) and cooled to -78 ° C. rac-x3 (270 mg, 0.60 mmol) was dissolved in CH ₂ CI ₂ (12 ml) and added. After stirring at rt for 1 h, the reaction mixture was added with acetone (10 ml) and warmed to rt and stirring was continued for 1 h. The solution was filtered through a frit with silica, rinsed with CH ₂ Cl ₂ (50 ml) and the solvent in vacuo away. After flash chromatography (EtOAc), rac-x4 was isolated as a yellowish solid (217 mg, 80%).

TLC: R _f = 0.40 in EtOAc;

^ -NMR (250 MHz, CDCI ₃ ,); δ = 7.77 (s, IH, H _N ), 5.65 (m, IH, H-l '), 5.60 (m, IH, H-2'), 5.20 (t, IH, H _Ger ), 5.02 (t, IH, H _Ger ), 4.56 (d, IH, H _Ger ), 4.35 (d, IH, HIGH,), 4.30 (d, IH, HIGH _b ), 3.90 (dd, IH, _Ger OCH _a ), 3.57 (dd , IH, _G e _r OCH _b ), 2.90 (m, IH, H-5), 2.77 (m, IH, H-4 _a ), 2.10-1.91 (m, 5H, H _Ger and H-4 _b ), 1.85-1.55 (m, 9H, H _Ger ); ¹³ C-NMR (63 MHz, CDCl3): δ = 159.0 (C4), 152.1 (C3 '), 150.8 (C2), 141.1 (C _Ger ), 139.3 (C6), 131.6 (C _Ger ), 126.3 (C _Ger ), 123.9 (C2 '), H7.4 (C _Ger ), 96.1 (C5), 63.6 ( _Ger OCH ₂ ), 61.0 (CH ₂ OH), 60.5 (Cl'), 47.2 (C4 '), 41.0 (C _Ger ), 39.6 (C _Ger ), 34.5 (C5 '), 26.4 (C _Ger ), 25.6 (C _Ger ). 17.7 (C _Ger ), 16.5 (C _Ger ); FT-IR (ATR): 3423 (s), 2912 (m), 1700 (s), 1645 (s), 1443 (s), 1382 (w), 1328 (w), 1234 (m), 1030 (m ), 759 (m); MS (ESI): 475 (100) [M + Na] ⁺ , 455 (73), 327 (17), 195 (2); HRMS (ESI) C ₂₁ H ₂₉ BrN ₂ O ₄ Na: calc. 475.1208, found. 475,121.

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M. Raisova, M. Bektas, T. Wieder, PT Daniel, 3rd level, CE Orfanos, CC Geilen (2000), Resistance to CD95 / Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release, FEBS Lett. 473, 27-32.

G. M. Cohen (1997), Caspases: the executioners of apoptosis, Biochem. J. 326, 1-16.

F. Eßmann, T. Wieder, A. Otto, E.-C. Müller, B. Dörken, P. T. Daniel (2000), The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.

E. Heßler, H.-G. Schmalz, G. Dürner (1994), Chiral Butadiene-Fe (CO) ₃ Complexes for Organic Synthesis. Reactions of (η ⁴ -2-alkoxy-4-vinyl-2,5-dihydrofuran) -Fe (CO) ₃ Derivatives, Tetrahedron Lett. 35, 4547-4550.

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Claims

claims: 1. Connection of structural formula 1:

With X = O, S, CH ₂ , NR, no bond Y = nucleobases, preferably purines or pyrimidines and their derivatives, particularly preferably adenine, cytosine, guanine, uracil, thymine, 5-bromouracil; halogenated nucleobases, heterocycles, aminoalkyl, aminoaryl or other residues capable of forming H-bonds, Z = alkyl (also branched and / or partially unsaturated) alkenyl, isoprenyl, geranyl, farnesyl, geranyl geranyl, and at least partially hydrogenated derivatives thereof, fluoroalkyl, aryl, fluoroaryl, POORHDR ² , - (CH ₂ ) _n OR ^' , with R ^' = H, SiR, SiR ^ R ³ , alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl; pronounced lipophilic residues, especially geranyl, farnesyl, fatty acid acyl or isoprenoid side chains, where R ¹ , R ² and R ³ are selected independently of one another from alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, especially geranyl, farnesyl, fatty acid acyl or isoprenoid side chains, R = CH ₂ OH, CH ₂ SH, COOR ^' (with R ^' = H, alkyl, aryl), CONR ₂ ^' (with R ^' = H, alkyl, aryl), CH ₂ NR'R "(with R ^' , R "= H, alkyl, aryl, acyl), CH = O, CH = NOR '(with R' = H, alkyl, aryl), R ≠ Z and, if R = CH ₂ OH and Z = t-budiphenylsilyl then Y ≠ uracil, with the proviso that when the compound is in the cis configuration and as a 'racemate, and X = CH ₂ ; and if R = CHO and Z = thexyl (CH ₃ ) ₂ SiO, then Y is not selected as indicated above, but is selected from the group purines and pyrimidines and their derivatives, halogenated nucleobases, aminoalkyl, aminoaryl, except adenine, bromourac .il, uracil, thymine or N-benzylcytosine; and if Y = adenine, R = CH ₂ OH, Z = - (CH ₂ ) _n OR \ and R ^'is a radical containing an Si, then R ¹ , R ² and R ^{3 are} not determined as indicated above, but are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, thexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, all also branched and / or partially unsaturated; Fluoroalkyl, aryl, fluoroaryl, acyl, as well as pronounced lipophilic residues, in particular geranyl, farnesyl, fatty acyl or isoprenoid side chains; and if R = CH ₂ OH and Z = thexyl (CH ₃ ) ₂ SiO, then Y is not selected as indicated above, but is selected from the group consisting of purines and pyrimidines and their derivatives, halogenated nucleobases, aminoalkyl, aminoaryl, except adenine and bromouracil. 2. Compound according to claim 1, characterized in that when the compound is in the cis configuration and as a racemate, and X = CH ₂ ; and if R - CHO and Z = thexyl (CH ₃ ) ₂ SiO, then Y is selected from the group consisting of derivatives of adenine, derivatives of uracil, derivatives of thymine, cytosine or derivatives of cytosine, guanine or derivatives of guanine, Imidazole, oxazole, thiazole, triazole and their derivatives and their partially or fully hydrogenated analogues); and if R = CH ₂ OH and Z = thexyl (CH ₃ ) ₂ SiO, then Y is selected from the group consisting of derivatives of adenine, cytosine or derivatives of cytosine, guanine or derivatives of guanine, uracil or derivatives of uracil, Thymine or derivatives of thymine or N-benzylcytosine, imidazole, oxazole, thiazole, triazole and their derivatives as well as their partially or fully hydrogenated analogues. 3. Compound according to claim 1 or 2 of structural formula 2:

cis-configured connections, of type xy or ent-xy, with R = H, SiR, SiR ¹ R ² R ³ , alkyl (also branched and / or partially unsaturated), fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, in particular geranyl, farnesyl, fatty acid acyl or isoprenoid side chains, where R ¹ , R ² and R ^{3 are} selected from alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, especially geranyl, farnesyl, fatty acyl or isoprenoid side chains. 4. A compound according to at least one of claims 1 to 3 of structural formula 2:

cis-configured connections of type xy or or ent-xy Y = adenine, guanine, cytosine, uracil, thymine, 5-bromouracil, 5-fluorouracil ,. R = thexyl (CH ₃ ) ₂ Si, ter £ -Bu (Ph) ₂ Si, 5. Connection according to at least one of claims 1 to 4 with one of the structural formulas:

(+) - 95b

(+) - 95e

(+) - 155a (+) - 155b

(+) - 155c (+) - 155d

(-) - 113a (-) - 113b

(-) - 113c (-) - 113d-l

(-) - 113d (-) - H3e

(-) - 159a C -) - 159b

(-) -! 59e-l (-) - 159c - 51 -

rac x4 6. Drugs of structural formula 1:

1 with X = O, S, CH ₂ , NR, no bond Y = adenine, cytosine, guanine, uracil, thymine, 5-bromouracil, purines or pyrimidines and their derivatives, nucleobases, halogenated nucleobases, heterocycles, aminoalkyl, aminoaryl or other residues capable of forming H-bonds, Z = alkyl (also branched and / or partially unsaturated) alkenyl, isoprenyl, geranyl, farnesyl, geranyl geranyl, and at least partially hydrogenated derivatives thereof, fluoroalkyl, aryl, fluoroaryl, POOR ^ OR ² , - (CH ₂ ) _n OR ', with R' =. H, SiR. SiR ¹ R ² R ³ , alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl; pronounced lipophilic residues, especially geranyl, farnesyl, fatty acyl or isoprenoid side chains, where R ¹ , R ² and R ^{3 are} selected from alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, especially geranyl, farnesyl, fatty acid acyl or isoprenoid Side chains, R = CH ₂ OH, CH ₂ SH, COOR '(with R' = H, alkyl, aryl), CONR ₂ ^' (with R ^' = H, alkyl, aryl), CH ₂ NR'R "(with R ', R "= H, alkyl, aryl, acyl), CH = O, CH = NOR '(with R ^' = H, alkyl, aryl). 7. Medicament according to claim 6 of structural formula 2:

cis-configured connections of type xy or ent-x, with R = H, SiR, SiR ¹ R ² R ³ , alkyl (also branched and / or partially unsaturated), fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, in particular geranyl, farnesyl, fatty acid acyl or isoprenoid side chains ^ where R ¹ , R ² and R ^{3 are} selected from alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, especially geranyl, farnesyl, fatty acyl or isoprenoid side chains. 8. Medicament according to one of claims 6 or 7 of structural formula 3:

2 eni-2 cis-configured compounds of the type xy or or ent-xy Y = adenine, guanine, cytosine, uracil, thymine, 5-bromouracil, 5-fluorouracil, R = thexyl (CH ₃ ) ₂ Si, tett-Bu ( Ph) ₂ Si, 9. Medicament according to at least one of claims 6 to 8 with one of the structural formulas:

+) - (+) -95b

(+) - 95e

(+) - 155a (+) - 155b

(+) - 155c (+) -155d

(-) - 113a (-) - H3b

(-) - 113d (-) - 113e

(-) - 159a (-) - 159b

(-) - 159c-l (-) - 159c

H 0

OH rac x4 10. Use of a compound of structural formula 1 for the manufacture of a medicament for the treatment of malignant diseases of the bone marrow or other hematopoietic organs, solid tumors, epithelial tumors, benign or semimalignant rapidly proliferating tumors or skin diseases, in particular psoriasis vulgaris, keloids and basaliomas, lymphomas, in particular Hodgkin - And non-Hodgkin's lymphomas, inflammatory, chronically inflammatory, bacterial and autoimmune diseases, for antibacterial, antifungal, anti-protozoa, anti-plasmodia, anti-helminthic, antiviral or immunosuppressive therapy and / or for triggering apoptosis, whereby in the Structural formula 1, the substituents have the following meaning:

1 X = O, S, CH ₂ , NR, no bond Y = adenine, cytosine, guanine, uracil, thymine, 5-bromouracil, purines or pyrimidines and their derivatives, nucleobases, halogenated nucleobases, heterocycles, aminoalkyl, aminoaryl or other residues capable of forming H-bridges, Z = alkyl (also branched and / or partially unsaturated) aikenyl, isoprenyl, geranyl, farnesyl, geranyl geranyl, and at least partially hydrogenated derivatives thereof, fluoroalkyl, aryl, fluoroaryl, POORkDR ² , - (CH ₂ ) _n OR ' , with R '= H, SiR ^, SiR ¹ R ² R ³ , alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl; pronounced lipophilic residues, especially geranyl, farnesyl, fatty acid acyl or isoprenoid side chains, wherein R ¹ , R ² and R ^{3 are} selected from alkyl (also branched and / or partially unsaturated); Fluoroalkyl, aryl, fluoroaryl, acyl, pronounced lipophilic residues, especially geranyl, farnesyl, fatty acid acyl. or chain isoprenoid sides, R = CH ₂ OH, CH ₂ SH, COOR ^' (with R' = H, alkyl, aryl), CONR ₂ ^' (with R' = H, alkyl, aryl), CH ₂ NR'R "(with R ', R "= H, alkyl, aryl, acyl), CH = O, CH = NOR '. (with R '= H, alkyl, aryl). 11. A process for the preparation of compounds according to any one of claims 1 to 5 or medicaments according to one of claims 6 to 9, characterized in that starting from a compound of the general structural formula 100, an acetal cleavage is carried out, and the aldehyde obtained by a reduction in the Alcohol is convicted. 12. The method according to claim 11, characterized in that the acetal cleavage with pyridine-p-toluenesulfonate (PPTS) and / or the reduction is carried out with sodium borohydride.