JP2003505459A - Process for the production of epothilone B and derivatives and intermediate products for this process - Google Patents

Abstract

  (57) [Summary] The present invention is directed to a process for the preparation of an epothilone compound, which comprises, as an improvement, preparing the compound by cyclization of a compound formed from an intermediate of formula (II) wherein PG is a protecting group.

Description

Detailed Description of the Invention

The present invention relates to a process for the production of epothilone B and derivatives, as well as intermediate products for this process. Natural substances epothilone A (R = H) and epothilone B (R = methyl) (compound I, DE 1954298
6A1, DE4138042C2):

[0002]

[Chemical 20] Is known to have fungicidal and cytotoxic effects.

[0003] The indicators of in vitro activity against breast and intestinal tumor cell lines indicate that compounds of this family are particularly advantageous for drug development. Efforts by various working groups have been successful in the synthesis of these macrocycles. In this regard, the Working Group is synthesizing the desired natural products starting from various fragments of the macrocycle. In all cases, diastereomeric pure fragments as starting and intermediate products are required for successful epothilone synthesis. Diastereomeric purity is often crucial to the action and reliability of a drug and consequently the requirements for its manufacture.

The total synthesis of epothilone A is described by Schinzer et al. In Chem. Eur. J. 1996, 2, No. 11, 1477-1.
482 and Angew. Chem. 1997, 109, No. 5, pp. 543-544. Epothilone derivatives have already been described in WO 97/19086 by Hofle et al. These derivatives were produced starting from natural epothilone A or B.

Another synthesis of epothilone and epothilone derivatives is described by Nicolaou et al. In Angew. Ch.
em. 1997, 109, No. 1/2, pp. 170-172. Nicolaou et al. Also described the synthesis of epothilone A and B and several epothilone analogs in Nature, Vol.
87, 1997, pp.268-272, and the synthesis of epothilone A and its derivatives in J. Am. Chem.
Soc., Vol. 119, No. 34, 1997, pp. 7960-7973, and Epothilone A and B and several epothilone analogues J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7
It is described in 991.

Nicolaou et al. Also described the formation of epothilone A analogs using coupled solid phase synthesis.
ngew.Chem.1997,109, No.19, pp.2181 to 2187. Some epothilone B
Analogues are also listed there. A variety of syntheses for the preparation of epothilone and different types of derivatives are known from WO 99/07692. Other syntheses are described in PCT patent applications WO 99/02514 and WO 99/01124.

Finally, mention may be made of the epothilone B-synthesis described by J. Mulzer et al. In Tetrahedron Letters 39 (1998) 8633-8636. Due to the expected instability of the epoxide, all previous epothilone B
In the synthesis, the corresponding (Z) -olefin is always epoxidized in the final step, whereby the diastereomers are 4: 1 to 20: 1 of the desired β-isomer.

The object of the present invention is to obtain a suitable (E) -olefin dihydroxylation, which allows the β-structure of the cis-epoxide to be produced from the previous dihydroxylation fairly early.
-To show a method for producing epothilone B and epothilone B derivatives in which cis-epoxide is introduced via monosulfonation. The other purpose is obvious in the light of one of the usual techniques.

[0009]   These objectives are represented by formula II:

[Chemical 21]

(Wherein TBS represents a tributylsilyl group). Instead of TBS, another suitable protecting group can also be used as the starting compound, which already contains the epoxy group of the epothilone, whereby this epoxy group remains unchanged in all successive reaction steps up to the final product. it can.

Diagram 3 shows the possible induction pathways acceptable for the method according to the invention when the compound 11 to be used and / or the next step 13 or 14 is modified as indicated. Therefore, the present invention extends not only to the method for producing epothilone B but also to the method for producing the corresponding modified derivative derived from the modified compound 11, 13 or 14. In addition, the invention also relates to the corresponding modified derivatives obtained by the procedure described above and shown in Diagram 3, as well as the compounds of formulas 5-21, which are all novel.

The choice of protecting group (PG) in the 15-hydroxy group can be taken by routine experimentation. The PG should continue all successive reactions until the macrolactonization, but also should be removable in the presence of the epoxide. The original TBS-functional group cannot be removed without destroying the substrate, however, after conversion of the 15-OTBS derivative to the 15-OTES analog (TES = triethylsilyl), an additional synthetic step Everything can be done easily. Other suitable groups can be routinely determined. TBS is preferably replaced by TES in steps 13, 14 or 15, and in steps 15 and 17-19 PG is preferably TES.

Thus, the early applied epoxides were shown to be stable under the following reaction conditions: 1. Reduction (neutral (DIBAH), ionic (selectride), metallic (Zn)) 2. Oxidation (osmium tetroxide-sodium periodate) 3. Base (fluoride, DMAP, LDA, enolate in aprotic solvent). In this case, it is particularly surprising that the C- and O-anions formed in the molecule at 1,5-intervals to the epoxide nucleus do not nucleophilically open the epoxide. 4. Electrophile (acylation with acid chloride in Yamaguchi reaction).

Of all the agents used, only the aqueous acid resulted in epoxide open chain. Apart from the mechanistically valuable discovery that escapes the prejudice that epoxides are highly reactive synthetic intermediates in all cases, the early introduction of epoxides also leads to the production according to the invention of epothilone B and the corresponding derivatives. Has considerable advantages. The N-oxide formation on thiazole seen in 12,13-epoxidation with peracid occurs just as the separation of 12,13-epimeric epoxide. "False"
No epoxide is formed. The stereoselectivity of the aldol reaction is also 21, 12, 13- (Z
) -Much higher than for olefin analogs. The example associated with Diagram 3 is used for a more detailed description of the invention.

Diagram 1 Synthesis of a fully functionalized C15-C7 fragment of epothilone B

[0016]

[Chemical formula 22]

A) O ₃ , CH ₂ Cl ₂ , -78 ° C, PPh ₃ ; b) Isopropenyl-MgBr, THF, -10 ° C; c) CH ₃ C (OEt) ₃ , xylene, 120 ° C, 12 hours d) DDQ, CH ₂ Cl ₂ -H ₂ O, rt; e) Dess-Martin periodinane, CH ₂ Cl ₂ , rt, 12 h; f) AD-mixed-β, tBuOH -H ₂ O, rt, 20 hours; g) Thz-CH ₂ -PBu ₃ Cl, KHMDS -78 ℃ then 30 ℃; h) MsCl, NEt ₃ , CH ₂ Cl ₂ , 0 ℃, 30 minutes; i) K ₂ CO ₃ , MeOH, rt, 45 minutes; k) DIBAH, CH ₂ Cl ₂ , -90 ° C, 1 hour;

L) LiOH (in situ), (EtO) ₂ POCH ₂ CO (N ⁰ ), then aldehyde, Et ₂ O-THF, rt, 30 min; m) L-selectride, THF -78 ° C., 1 Time, then HMPA, mel, from -78 ° C to 0 ° C,
4 hours; n) DIBAH, CH ₂ Cl ₂ , -80 ° C to -70 ° C, 2 hours. Bn = benzyl, PMB = p-methoxy-benzyl. All selectrides (see Aldrich Chemical catalog) can be used in this method. L-Selectride (lithium-tri-s-butylborohydride) is preferred.

Diagram 2 Total Synthesis of Epothilone B (Epoxide Route)

[0020]

[Chemical formula 23]

A) LDA, THF, -78 ° C; b) TrocCl, pyridine, CH ₂ Cl ₂ , rt; c) i.OsO ₄ , NMO; ii) NaIO ₄ ; d) HF-Py, pyridine rt; e ) NaClO ₂ , NaH ₂ PO ₄ , tBuOH, 2,3-dimethyl-2-butene; f) 2,4,6-trichlorobenzoyl chloride, NEt ₃ , then DMAP, toluene; g) HF-Py, pyridine rt _{; h) Zn, NH 4 Cl} , EtOH, reflux, 30 minutes. Ketone 16 K.C. Nicolaou et al .: J. Am. Chem. Soc. 1997, 119, 7974-7991.

Diagram 3 Derivative pathway

[Chemical formula 24]

[0023]

[Chemical 25]

It is believed that one of ordinary skill in the art, using the preceding description, could utilize the invention to its full extent, without further finishing. Therefore, the following preferred specific embodiments are considered merely illustrative and in any way
It is not intended to limit the balance of the disclosure. In the examples above and hereafter, all temperatures are given in degrees Celsius without correction, and all parts and percentages are by weight unless otherwise indicated. The complete disclosures of all patent applications, patents and publications cited above, and US Provisional Application No. 60,145,005, filed July 22, 1999, are hereby incorporated by reference.

[0025]     Example Experiment

[Chemical formula 26]

8.02 g (25 mmol) of alkene 3a was dissolved in 200 ml of anhydrous methylene chloride to give anhydrous MeOH1.
Mix with 0 ml. After cooling to -78 ° C, the dry ozone / air mixture is introduced via a gas feed frit until the blue coloration begins. Air is bubbled in for more than 2 minutes, then quenched by the addition of 19.67 g (75 mmol) of PPh ₃ and left to thaw overnight. The solvent was removed as completely as possible in a Rotavapor and the solid residue that remained was subjected to preparative column chromatography (hexane / ethyl acetate / methylene chloride = 40: 1: 1, then Hx / EE 20: 1-10). 1) is used to separate PPh ₃ . 7.90g (98%
) Aldehyde 4a is obtained as a colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (dd, J = 1.5, 2.0 Hz, 1 H); 7.34-7.24 (m, 5 H), 4
.58 (d, J = 11.8Hz, 1H), 4.45 (d, J = 11.8Hz, 1H), 4.31 (dt, J = 6.3, 4.5Hz, 1H),
3.58-3.51 (m, 1H), 2.69-2.62 (m, 1H), 2.51-2.43 (m, 1H), 1.14 (d, J = 6.3Hz,
3H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 201.8, 138.4, 128.4, 127.6, 71.0, 68.9, 46.0,
25.7, 17.9, 13.5, -4.7, -4.9. IR (Film): v _max 2956, 2857, 2712, 1730, 1472, 1255, 1102, 837, 778cm ^-1 .

[0028]

[Chemical 27]

75 ml of isopropenyl magnesium bromide (0.5 M, THF) and 25 ml of anhydrous THF were cooled to -10 ° C under Ar atmosphere, and 9.14 g (28.3 mmol) of aldehyde 4a (dissolved in 20 ml of anhydrous THF) was added to -10. Add slowly (about 20 minutes) drop-wise at ° C. Leave it for 45 minutes to thaw and then 0
C. (TLC monitor, Grignard must also be added arbitrarily), the reaction mixture is poured into 150 ml of semisaturated NH ₄ Cl solution and 120 ml of ether are shaken after addition.
The aqueous phase is extracted twice more with ether (100 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 10: 1) produces 9.48 g (92%) of allyl alcohol 5a (mixture of diastereomers) as a colorless viscous liquid.

Diastereomer 1 ¹ H NMR (400 MHz, CDCl ₃ ) δ7.34-7.24 (m, 5H), 4.98 (s, 1H), 4.80 (s, 1H), 4.6
0 (d, J = 12.0Hz, 1H), 4.53 (d, J = 12.0Hz, 1H), 4.17 (d _br , J = 9.5Hz, 1H), 4.02 (
dt, J = 7.4, 4.5Hz, 1H), 3.61-3.54 (m, 1H), 2.71 (d _br , J = 3.5Hz, 1H), 1.84-1.
75 (m, 1H), 1.72 (s, 3H), 1.65-1.57 (m, 1H), 1.14 (d, J = 6.5Hz, 3H), 0.86 (s,
9H), 0.05 (s, 3H), -0.02 (s, 3H).

Diastereomer 2 ¹ H NMR (400 MHz, CDCl ₃ ) δ7.34-7.24 (m, 5H), 4.99 (s, 1H), 4.83 (s, 1H), 4.6
0 (d, J = 12.0Hz, 1H), 4.47 (d, J = 12.0Hz, 1H), 4.20 (dd, J = 8.0, 3.5Hz, 1H), 3
.90 (dt, J = 8.5, 4.3Hz, 1H), 3.47 (dq, J = 6.4, 4.3Hz, 1H), 2.97 (s _br , 1H), 1.
86 (dt, J = 14.2, 4.1Hz, 1H), 1.67 (s, 3H), 1.57 (dt, J = 14.6, 8.5Hz, 1H), 1.1
0 (d, J = 6.4Hz, 3H), 0.80 (s, 9H)

[0032]

[Chemical 28]

8.02 g (22 mmol) of allyl alcohol 5a (mixture of diastereomers) was added to anhydrous xylene.
Dissolve in 120 ml and mix with 32 ml (176 mmol) triethyl orthoacetate and 4 drops propionic acid. Stir for 16-20 hours at 120 ° C. with a stream of Ar shining through a thin capillary, the ethanol produced thereby being distilled off via a small distillation apparatus. Once the reaction is complete (TLC monitor), the solvent is placed in rotavapor (30 mbar, 5 mbar).
The crude product was separated by distillation at 0 ° C, then complete vacuum) and the crude product was subjected to column chromatography (Hx / EE = 4
Purify by 0: 1 gradient 20: 1). 8.77 g (92%) of 6a is obtained as a colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.22 (m, 5 H); 5.20 (t, J = 6.4 Hz, 1 H); 4.57 (d,
J = 12Hz, 1H), 4.48 (d, J = 12Hz, 1H), 4.11 (q, J = 7.2, 2H), 3.68 (m, J = 4Hz, 1H
), 3.46 (dt, J = 6.3, 4.5Hz, 1H), 2.40-2.34 (m, 1H), 2.32-2.24 (m, 2H), 2.14-
2.04 (m, 1H), 1.60 (s, 3H), 1.23 (t, J = 7.2Hz, 2H), 1.11 (d, J = 6.4Hz, 3H), 0.
84 (s, 9H), -0.02 (s, 3H), -0.05 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 173.5, 139.1, 134.5, 128.2, 127.5, 127.4, 124
.0, 122.4, 77.3, 74.0, 71.0, 60.2, 34.8, 33.1, 30.1, 25.8, 18.0, 16.1, 1
4.2, 14.0, -4.60, -4.61. IR (Film): v _max 2956, 2930, 2887, 2857, 1737, 1472, 1462, 1454, 1370, 1
300, 1255, 1155, 1098, 939, 836, 776, 737cm ^-1 .HRMS (EI) Cld. For C ₂₅ H ₄₂ O ₄ Si 434.2852, Fnd. 434.2845 [α] ²⁰ _D = -3.9 (c = 1.2. CHCl ₃ )

[0035]

[Chemical 29]

912 mg (2.10 mmol) of 6a was dissolved in 40 ml of methylene chloride and 2 ml of water to give 2.86 g of DDQ (
12.6 mmol) and vigorously stirred at room temperature for exactly 3 hours. The reaction mixture is diluted with 100 ml ether and washed with NaHCO ₃ (aq, sat) (2 × 40 ml). The combined aqueous phase is diluted with 80 ml of water and extracted with ether (2 x 50 ml). Combine the organic phases with brine (50
washed with ml), dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 10: 1) yields 575 mg (80%) of alcohol 7 as a colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.16 (dt, J = 7.3, 1.0 Hz, 1 H), 4.09 (q, J = 7.07 Hz, 2
H), 3.56 (m, 1H), 3.42 (dt, J = 7.2, 4.4Hz, 1H), 2.40-2.26 (m, 5H), 2.15-2.07
(m, 2H), 1.61 (m, 3H), 1.23 (t, J = 7.0Hz, 3H), 1.09 (d, J = 6.5Hz, 3H), 0.88 (s
, 9H), 0.06 (s, 6H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 173.7, 136.1, 120.9, 77.0, 69.0, 60.7, 35.2,
33.5, 33.0, 26.2, 20.3, 18.5, 16.6, 14.6, -3.8, -4.3. IR (Film): v _max 3513 (br), 2932, 2874, 2855, 1738, 1463, 1372, 1255, 115
7, 1088, 836, 777cm ^-1 .HRMS (EI) Cld. For (M ⁺ -C ₄ H ₉ ) 287.168, Fnd. 287.168 ± 5ppm [α] ²⁰ _D = -20.2 (c = 1.08, CHCl ₃ )

[0038]

[Chemical 30]

1.030 g (2.99 mmol) of alcohol 7 was dissolved in 50 ml of anhydrous methylene chloride and mixed with 2.5 ml of anhydrous pyridine and 2.54 g (6.0 mmol) of Dess-Martin periodinane at room temperature. Stir overnight (about 18 hours). To stimulate it is mixed with 25 ml of sodium thiosulfate solution (20% aqueous solution) and it is stirred vigorously for 15 minutes. The phases are separated and the aqueous phase is extracted with methylene chloride (2 x 25 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 10: 1) yields 945 mg (92%) of ketone 8 as a colorless liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.15 (t, 1 H, J = 6.8 Hz, 1 H); 4.10 (q, J = 7.0 Hz, 2 H),
3.97 (dd, J = 6.5, 5.5Hz, 1H), 2.40-2.20 (m, 6H), 2.12 (s, 3H), 1.59 (s, 3H),
1.23 (t, J = 7.0Hz, 1H), 0.89 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 212.5, 173.7, 137.0, 119.7, 79.2, 60.7, 35.1,
33.9, 33.7, 33.4, 26.1, 25.9, 18.5, 16.6, 14.6, -4.5, -4.6. IR (Film): v _max 2932, 2875, 2858, 1737, 1351, 1256, 1203, 1160, 1137, 110
2, 959, 927, 899, 839, 779cm ^-1 .HRMS (EI) Cld. For (M ⁺ -CH ₃ ) 327.1992.Fnd. 327.199 ± 0.0016 [α] ²⁰ _D = -19.4 (c = 1.05, CHCl ₃ )

[0041]

[Chemical 31]

A) 830 mg (2.42 mmol) of 8 was dissolved in 30 ml of tBuOH-H ₂ O (1: 1), NaHCO ₃ 1.5 g, AD-mixed (Mix) -β 5.0 g and methanesulfonamide 230 mg. Mix with. After stirring vigorously at room temperature for 36-48 hours, add 5 g of sodium sulfite to cool it (1
0 minutes or more). After adding 25 ml H ₂ O and 100 ml methylene chloride, the phases are separated and the aqueous phase is extracted with methylene chloride (3 × 30 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 2: 1, R _{j (3: 1)} =
0.09-0.29) yields 942 mg of mixed product 8a.

IR (film): V _max 3432,2933,2858,1736,1377,1256,1229,1095,837,778 cm ^-1 .b) 1.82 g of Wittig salt (5.2 mmol) anhydrous THF under Ar atmosphere 30 ml Dissolve in
Cool to -78 ° C, add 10.4 ml of KHMDS (0.5M, toluene) dropwise and stir at -78 ° C for 45 minutes. Then 920 mg of 8a (dissolved in 2.5 ml of THF) are added smoothly and in drops. It is left to stir at -78 ° C for 5 minutes or more, then the cooling bath is quickly replaced with a water bath at about 40 ° C and left to thaw. After 5 minutes, the bath is removed, it is left to stir for a further 5 minutes and then quenched with 50 ml NH ₄ Cl (saturated aqueous solution) and 75 ml ether. The aqueous phase is extracted with ether (2 x 30 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. 6 by preparative column chromatography (Hx / EE = 2: 1)
32 mg (61% in both synthetic steps) of alkene 9 are produced as a colorless viscous liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ6.93 (s, 1H), 6.47 (s, 1H), 4.41 (dd, J = 8.5, 4.5 Hz
, 1H), 3.67 (d, J = 10.0Hz, 1H), 3.45 (s, 1H), 2.71-2.61 (m, 1H), 2.68 (s, 3H)
, 2.66-2.46 (m, 1H), 2.37-2.28 (m, 1H), 1.99 (s, 3H), 1.80-1.66 (m, 2H), 1.7
0 (dd, J = 14.3, 4.8Hz, 1H), 1.34 (s, 3H), 0.88 (s, 9H), 0.10 (s, 3H), 0.01 (s,
3H).

¹³ C NMR (100.6 MHz CDCl ₃ ) δ 177.6, 165.1, 152.9, 141.4, 120.4, 116.3, 88.
0, 79.9, 76.7, 37.1, 30.9, 29.9, 26.2, 23.6, 19.6, 18.4, 14.1, -4.0, -4.
8. IR (Film): v _max 3469, 2955, 2943, 2930, 2910, 2892, 2856, 1768, 1656, 1
505, 1462, 1386, 1252, 1066, 838cm ^-1 .HRMS (EI) Cld. For C21H35NO4SiS 425.2056 Fnd. 425,2060 ± 0.0025 [α] ²⁰ _D = -27.1 (c = 1.0, CHCl ₃ )

[0046]

[Chemical 32]

313 mg (0.737 mmol) of alcohol 9 was dissolved in 5 ml of anhydrous methylene chloride under Ar atmosphere, 0.31 ml of anhydrous triethylamine and 0.09 ml of methanesulfonic acid chloride were prepared at 0 ° C.
Mix with. After 30 minutes, quench with 10 ml of NaHCO ₃ (saturated aqueous solution), the phases are separated and the aqueous phase is extracted with methylene chloride (3 × 10 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. 2 by preparative column chromatography (Hx / EE = 4: 1)
83 mg (76%) of mesylate 10 are produced as a highly viscous yellow liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ6.96 (s, 1H), 6.56 (s, 1H), 4.57 (dd, J = 8.0, 2.5 Hz
, 1H), 4.41 (dd, J = 8.8, 4.8Hz, 1H), 3.13 (s, 3H), 2.68 (s, 3H), 2.60-2.53 (m
, 2H), 2.02 (d, J = 1.0Hz, 3H), 2.07-1.81 (m, 4H), 1.42 (s, 3H), 0.87 (s, 9H),
0.08 (s, 3H), 0.02 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 175.5, 165.0, 153.2, 138.7, 122.1, 117.2, 86.
5, 83.8, 75.7, 39.6, 38.0, 31.2, 28.8, 26.2, 21.7, 19.7, 18.5, 13.1, -4.
3, -4.6.

[0049]

[Chemical 33]

256 mg (0.508 mmol) of mesylate 10 is dissolved in 10 ml of anhydrous methanol and mixed with finely ground fine potassium carbonate. After 45 minutes at room temperature dilute it with 30 ml ether,
Then filter. Saturated NH ₄ Cl solution (15 ml) is added to the filtrate until two clear phases are formed. The phases are separated and the aqueous phase is extracted with ether (3 x 10 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 5: 1) yields 202 mg (90%) of epoxide 11 as a colorless viscous liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ6.91 (s, 1H), 6.49 (s, 1H), 4.32 (dd, J = 9.0, 3.5 Hz
, 1H), 3.65 (s, 3H), 2.89 (dd, J = 7.0, 4.5Hz, 1H), 2.68 (s, 3H), 2.46-2.40 (m
, 2H), 1.99 (d, J = 1.5Hz, 1H), 1.94-1.77 (m, 3H), 1.63-1.55 (m, 1H), 1.26 (s,
3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 173.6, 164.9, 153.4, 142.4, 119.3, 115.8, 76.
7, 62.8, 60.4, 52.1, 36.3, 30.5, 28.6, 26.3, 22.5, 19.6, 18.6, 14.4, -4.
2, -4.7. IR (Film): v _max 2955, 2874, 2857, 1740, 1656, 1505, 1439, 1380, 1312, 1
230, 1180, 1077, 835, 778cm ^-1 .HRMS (EI) Cld. For C ₂₂ H ₃₇ NO ₄ SiS 439.2213 Fnd. 439.221 ± 0.0025. [Α] ²⁰ _D = -12.6 (c = 1.04, CHCl ₃ )

[0052]

[Chemical 34]

176 mg (0.40 mmol) of Epoxide 11 was dissolved in 6 ml of anhydrous MC under argon and -95 ° C.
Slowly (about 5 minutes) mix with 0.29 ml (0.44 mmol) DIBAH (1.5 M toluene). It is mixed with 0.15 ml of NH ₄ Cl solution and 10 ml of ether with vigorous stirring, allowed to reach −85 ° C. within 45 minutes and left to thaw rapidly. After adding sufficient MgSO ₄ ,
It is left to stir for 1-2 hours and filtered off. After removing the solvent in rotavapor, the crude aldehyde was purified by column chromatography (Hx / EE = 3: 1) to give 140 mg (8
5%) of aldehyde 11a is obtained as a colorless oil. IR (Film): Vmax2930,2781,1727,1677,1076,919,836.

[0054]

[Chemical 35]

4 ml of anhydrous ether at 0 ° C. and 0.32 ml of nBuLi (1.6 M, hexane, 0.51 mmol) in Ar
Introduced under an atmosphere, THF / H ₂ O: mixed with (19 1, H ₂ O1m mol) 0.36 ml. After 5 minutes, 193 mg of phosphonate (0.49 mmol, dissolved in 1 ml of THF) was added dropwise and after a further 10 minutes,
135 mg of aldehyde 11a (0.33 mmol, dissolved in 1 ml of THF) are added dropwise. The cooling bath is removed and after 30 minutes at room temperature it is quenched with 4 ml saturated NH ₄ Cl solution, the phases are separated and the aqueous phase is extracted with ether (2 × 5 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. 194mg by preparative column chromatography (Hx / EE = 3: 1)
(91%) Enoylsultam 12 is produced as a viscous oil which solidifies like a foam after freezing.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (dt, J = 14.8, 7.3 Hz, 1H), 6.91 (s, 1H), 6.55 (
d, J = 14.8Hz, 1H), 6.49 (s, 1H), 4.32 (dd, J = 8.8, 3.8Hz, 1H), 3.90 (dd, J = 7.
3, 5.3Hz, 1H), 3.48 (d, J = 13.8Hz, 1H); 3.40 (d, J = 13.8Hz, 1H), 2.89 (dd, J =
7.5, 4.5Hz, 1H), 2.68 (s, 3H), 2.42-2.33 (m, 2H), 2.13-2.02 (m, 2H), 1.99 (s
, 3H), 1.95-1.81 (m, 5H), 1.71-1.51 (m, 4H), 1.27 (s, 3H), 1.14 (s, 3H), 0.9
5 (s, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 164.8, 164.3, 153.4, 149.9, 142.4, 121.6 , 119
.3, 115.8, 76.8, 65.5, 62.6, 60.7, 53.5, 50.7, 48.8, 48.2, 45.1, 38.9, 3
6.2, 33.3, 31.9, 28.8, 26.9, 26.2, 22.6, 21.2, 20.3, 19.6, 18.6, 14.4,-
4.2, -4.7.

[0057]

[Chemical 36]

172 mg (0.265 mmol) of Sultam 12 was dissolved in 5 ml of anhydrous THF and 0.32 ml of L-at -95 ° C.
Mix with Selectride (1.0M, THF, 0.32mMole) and heat to -40 ° C within 45 minutes. After an additional 15 minutes, cool it to -78 ° C, add 0.12 ml of HMPA, then add 0.132 ml of MeI.
Mix with. Then heat it to 0 ° C within 3 hours and after 2 hours at 0 ° C add 5ml.
Quench it by adding 10 mL of NH ₄ Cl and ether. The phases are separated and the aqueous phase is extracted with ether (2 x 5 ml). The combined organic phases were dried (MgSO _4), removed the solvent in rotavapor. Preparative column chromatography (Hx / EE = 3: 1) yields 90 mg of compound 13 and 85 mg of compound 14.

Compound 13 ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.88 (s, 1 H), 6.47 (s, 1 H), 4.29 (dd, J = 9.0, 3.5 Hz)
, 1H), 3.85 (t, J = 6.3Hz, 1H), 3.44 (d, J = 13.5Hz, 1H), 3.37 (d, J = 3.5Hz, 1H)
, 3.07-3.97 (m, 1H), 2.83 (dd, J = 8.0, 4.0Hz, 1H), 2.66 (s, 3H), 2.02-1.98 (m
, 2H), 1.98 (d, J = 1.0Hz, 3H), 1.92-1.68 (m, 5H), 1.57-1.26 (m, 8H), 1.22 (s,
3H), 1.16 (d, J = 7.0Hz, 3H), 1.11 (s, 3H), 0.92 (s, 3H), 0.86 (s, 9H), 0.05 (
s, 3H), -0.01 (s, 3H).

Compound 14 ¹ H NMR (400 MHz, CDCl ₃ ) δ6.91 (s, 1H), 6.49 (s, 1H), 4.31 (dd, J = 9.0, 3.5 Hz
, 1H), 3.83, (dd, J = 7.3, 5.3Hz, 1H), 3.45 (d, J = 13.6Hz, 1H), 3.39 (d, J = 13
.6Hz, 1H), 2.86 (dd, J = 7.8, 4.3Hz, 1H), 2.75-2.63 (m, 2H), 2.68 (s, 3H), 2.
12-2.03 (m, 2H), 2.00 (d, J = 1.0Hz, 3H), 1.93-1.80 (m, 4H), 1.72-1.30 (m, 9H)
, 1.24 (s, 3H), 1.12 (s, 3H), 0.93 (s, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.01 (
s, 3H).

[0061]

[Chemical 37]

50 mg (0.075 mmol) sultam 13 is dissolved in 2.5 ml anhydrous methylene chloride under argon and slowly mixed at −95 ° C. with 0.083 ml (0.083 mmol) DIBAH (1.0 M, toluene). It is left to reach −75 ° C. within 2-2.5 hours with vigorous stirring with 0.05 ml MeOH and 0.1 ml NH ₄ Cl solution and 5 ml ether, which is left to thaw quickly. After adding sufficient MgSO ₄ , it is left to stir for about 1 hour (even overnight) and filtered off. After removing the solvent in rotavapor, the crude aldehyde is purified by preparative column chromatography (Hx / EE = 3: 1) to give 24 mg (71%) of aldehyde 15 as a waxy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (d, J = 5.0 Hz, 1 H), 6.90 (s, 1 H), 6.49 (s, 1 H),
4.31 (dd, J = 9.0, 4.0Hz, 1H), 2.87 (dd, J = 7.0, 4.5Hz, 1H), 2.68 (s, 3H), 2.
36-2.26 (m, 1H), 2.00 (s, 3H), 1.92-1.84 (m, 1H), 1.74-1.64 (m, 1H), 1.60-1.
52 (m, 1H), 1.50-1.32 (m, 5H), 1.26 (s, 3H), 1.08 (d, J = 7.0Hz, 3H), 0.88 (s,
9H), 0.07 (s, 3H), 0.01 (s, 3H). ¹³ C NMR (100.6MHz CDCl ₃ ) δ 205.2, 164.9, 153.4, 142.5, 119.2, 115.8, 76.
7, 62.4, 61.1, 46.7, 36.4, 33.6, 31.0, 26.2, 23.3, 22.7, 19.6, 18.6, 14.
4, 13.7, -4.2, -4.7.

Aldol reaction

[Chemical 38]

1.75 ml (1.23 mmol) isopropylamine was dissolved in 4 ml anhydrous THF and stirred at -45 ° C.
Mix with 75 ml of nBuLi (1. 6M in hexane, 1.20 mmol), heat to 0 ° C after 5 minutes, and heat at 0 ° C for 20 min.
Stir for minutes. After cooling to −78 ° C., 345 mg (1.21 mmol) of ketone 16 (dissolved in 1 ml THF) are added dropwise within 2 minutes and the reaction mixture is heated to −40 ° C. within 30 minutes. It was cooled again to -78 ° C and 532 mg (1.18 mmol) of aldehyde 15 (dissolved in 1.5 ml of THF) was added.
Add in droplets within ~ 3 minutes.

After 15 minutes at −78 ° C., quench it with 4 ml of saturated NH ₄ Cl solution with vigorous stirring (first slowly and quickly afterwards), add 6 ml of ether and replace the cooling bath with a water bath. . After thawing some water is added and after shaking the phases separate. Extraction with ether, dried (MgSO _4), removal and subsequent column chromatography solvents (hexane /
Ethyl acetate 10: 1 → 5: 1) yields 668 mg (77%) of the desired major isomer 17 as a colorless viscous liquid.

Compound 17 (R ² = TES, R ³ = TBS) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.93 (s, 1H), 6.51 (s, 1H), 5.72 (ddt, J = 17.1, 10
.0, 7.0Hz, 1H), 4.99 (m, 2H), 4.33 (dd, J = 9.0, 3.5Hz, 1H), 3.92 (d, J = 6.3,
4.3Hz, 1H), 3.49 (s, 1H), 3.31 (d, J = 9.0Hz, 1H), 3.25 (q, J = 7.0Hz, 1H), 2.8
8 (dd, J = 7.5, 4.0Hz, 1H), 2.70 (s, 3H), 2.24-2.06 (m, 2H), 2.01 (d, J = 1.0Hz,
3H), 1.95-1.87 (m, 1H), 1.82-1.72 (m, 1H), 1.63-1.45 (m, 5H), 1.41-1.30 (m,
1H), 1.28 (s, 3H), 1.18 (s, 3H), 1.20-1.05 (m, 1H), 1.12 (s, 3H), 1.03 (d, J
= 7.0Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.83 (d, J = 7.0Hz, 3H), 0.09 (s, 3H)
, 0.07 (s, 3H), 0.06 (s, 3H), 0.03 (m, 3H), ¹³ C NMR (100.6MHz, CDCl ₃ ): δ = 2
22.5, 164.4, 153.1, 142.2, 136.3, 118.8, 116.7, 115.3, 76.5, 76.4, 74.9,
62.1, 61.1, 54.3, 41.1, 39.6, 36.0, 35.6, 33.4, 33.1, 26.05, 25.9, 23.4
, 22.7, 22.4, 19.4, 19.2, 18.24, 18.21, 15.3, 14.0, 9.7, -3.5, -4.90, -4
.6, -5.1.

[0068]

[Chemical Formula 39]

200 mg (0.27 mmol) of aldol 17 was dissolved in 10 ml of methylene chloride and 5 ml of pyridine, and at 20 ° C. (water bath) 0.5 ml of chloroformic acid-2,2,2-trichloroethyl ester (2.4 m
Mol) and stir at room temperature for 30-45 minutes. To stimulate, the reaction mixture is shaken with 50 ml saturated NaHCO ₃ solution and 40 ml methylene chloride. Extraction with methylene chloride, dried (MgSO _4), removal and subsequent column chromatography solvents (hexane / ethyl acetate 10: 1), to produce the desired product 18 in 231 mg (94%) as a colorless oil.

Compound 18 (R ² = TES, R ³ = TBS, R ⁴ = Troc) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.92 (s, 1H), 6.51 (s, 1H), 5.79 (ddt, J = 16.6, 10
.5, 7.0Hz, 1H), 5.05-4.97 (m, 2H), 4.85 (d, J = 12.1Hz, 1H), 4.81 (dd, J = 7.0,
4.5Hz, 1H), 4.69 (d, J = 12.1Hz, 1H), 4.33 (dd, J = 9.0, 3.5Hz, 1H), 3.75 (dd,
J = 6.5, 4.0Hz, 1H), 3.44 (m, 1H), 2.88 (dd, J = 7.5, 4.0Hz, 1H), 2.70 (s, 3H)
, 2.28-2.19 (m, 1H), 2.06-1.95 (m, 1H), 2.02 (s, 3H), 1.92-1.84 (m, 1H), 1.7
5-1.65 (m, 1H), 1.57-1.41 (m, 5H), 1.33-1.11 (m, 2H), 1.30 (s, 3H), 1.27 (s,
3H), 1.21-1.12 (m, 1H), 1.07 (d, J = 7.0Hz, 3H), 1.04 (s, 3H), 0.96 (d, J = 7.0H
z, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H),
0.03 (s, 3H), ¹³ C NMR (100.6MHz, CDCl ₃ ): δ = 215.6, 164.4, 154.2, 153.1, 1
42.1, 136.4, 118.9, 116.6, 115.4, 94.8, 82.9, 78.1, 76.6, 76.4, 62.1, 60
.8, 54.0, 42.3, 39.4, 36.0, 35.0, 33.3, 31.8, 26.1, 25.9, 24.0, 22.7, 22
.3, 20.0, 19.2, 18.23, 18.21, 16.1, 14.0, 11.5, -3.6, -3.9, -4.6, -5.1.
IR (film): ν _max = 2956, 2930, 2858, 1760, 1699, 1472, 1384, 1251, 1081, 992
, 928, 836, 777, 732. Rotation: [α] ²⁰ _D = -30 (c = 1.4, CH ₂ Cl ₂ ). Analysis Cl
d. for C ₄₃ H ₇₄ Cl ₃ NO ₇ SSi ₂ (911,65): C 56.65, H 8.18, N 1.54, Fnd .: C 56.54
H 8.18 N 1.47.

[0071]

[Chemical 40]

148 mg (0.162 mmol) alkene 18 was dissolved in 8 ml THF-tBuOH (1: 1) and 2 mg OsO ₄ (
5 mol%) and 0.89 ml NMO (0.2 M in H ₂ O, 0.178 mmol). Stir at 25 ° C 1
After 6 hours it is shaken vigorously for a long time with 10 ml Na ₂ S ₂ O ₃ (10% in H ₂ O) and 15 ml methylene chloride. The phases are separated and the aqueous phase is extracted three times more with methylene chloride. Dry (MgSO ₄ ), remove solvent and short silica gel column (hexane /
Filtration through ethyl acetate 1: 1) yields 131 mg (86%) of the diol as a mixture of isomers which is used further without further purification.

131 mg (0.139 mmol) of the diol was dissolved in 15 ml of ethanol and 3 ml of H ₂ O and NaI
Mix with 90 mg O ₄ (0.420 mmol). After 3 hours of stirring at 25 ° C. it is shaken with 30 ml of semisaturated NaHCO ₃ solution and 30 ml of ether and the phases are separated. Extraction with ether,
Drying (MgSO ₄ ), removal of solvent and subsequent column chromatography (hexane / ethyl acetate 10: 1 → 5: 1) yields 115 mg (78% as alkene) of aldehyde 19 as a colorless oil.

Compound 19 (R ² = TES, R ^{3 ′} = TBS, R ⁴ = Troc) ¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.73 (dd, J = 2.0, 1.0Hz, 1H), 6.92 ( s, 1H), 6.50
(s, 1H), 4.83 (d, J = 12.0Hz, 1H), 4.74 (dd, J = 7.5, 4.0Hz, 1H), 4.67 (d, J = 11
.8Hz, 1H), 4.36-4.29 (m, 2H), 3.49-3.38 (m, 1H), 2.88 (dd, J = 7.5, 4.0Hz, 1H
), 2.70 (s, 3H), 2.67 (ddd, J = 17.5, 4.5, 1.0Hz, 1H), 2.39 (ddd, J = 17.5, 5.5
, 2.0Hz, 1H), 2.39 (s, 3H), 1.88 (ddd, J = 13.9, 9.4, 4.0Hz, 1H), 1.76-1.66 (
m, 1H), 1.60-1.40 (m, 5H), 1.35-1.10, (m, 2H), 1.33 (s, 3H), 1.26 (s, 3H),
1.20 (d, J = 6.5Hz, 1H), 1.02 (s, 3H), 0.97 (d, J = 6.5Hz, 3H), 0.90 (s, 9H), 0.
86 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), ¹³ C NMR (
100.6MHz, CDCl ₃ ): δ = 215.4, 200.2, 164.2, 154.2, 153.0, 142.1, 118.9, 115
.4, 94.7, 82.3, 76.65, 76.3, 72.3, 62.1, 60.8, 53.4, 49.3, 42.2, 35.9, 3
4.9, 3.33, 31.9, 25.87, 25.85, 23.0, 22.6, 22.3, 20.0, 19.2, 18.2, 18.1,
15.9, 14.0, 11.1, -4.4, -4.5, -4.6, -5.1. IR (Film): ν _max = 2956, 2930, 2
885, 2857, 1759, 1726, 1699, 1472, 1384, 1361, 1252, 1082, 992, 927, 836
, 777, 734. Rotation: [α] ²⁰ _D = -42.7 (c = 1.2, CHCl ₃ ).

[0075]

[Chemical 41]

68 mg (0.074 mmol) of 19 are dissolved in 2.5 ml of anhydrous THF in a polypropylene reactor (with lid) and 2.5 ml of HF-pyridine standard solution buffered with pyridine (HF-pyridine 5 ml,
Mixed with 15 ml of pyridine and 10 ml of THF). After 30 minutes, the reaction is complete. To stimulate 80 ml saturated NaHCO ₃ solution are introduced and the reaction mixture is carefully added with vigorous stirring (plastic syringe). After extraction with ether ( ₄ x 25 ml) and drying (MgSO4), the solvent is removed in rotavapor, whereby the pyridine is removed by repeated spinning-in with toluene. The residue is loaded on a deactivated silica gel column (hexane / ethyl acetate 2: 1 → 1: 1) to give 51 mg (92%) of product 20 as a pale yellow viscous oil. Compound 20 (R ³ = TBS, R ⁴ = Troc)

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.74 (s, 1H), 6.95 (s, 1H), 6.60 (s, 1H), 4.84 (d,
J = 12.0Hz, 1H), 4.75 (dd, J = 7.8, 4.3Hz, 1H), 4.68 (d, J = 12.0Hz, 1H), 4.41-
4.35 (m, 1H), 4.34 (t, J = 4.8Hz, 1H); 3.49-3.41 (m, 1H), 2.96 (dd, J = 8.0, 4.0
Hz, 1H), 2.96 (s, 3H), 2.67 (dd, J = 17.5Hz, 4.0Hz, 1H), 2.40 (ddd, J = 17.5, 5
.5, 2.0Hz, 1H), 2.09 (d, J = 3.5Hz, 1H), 2.06 (s, 3H), 1.94 (ddd, J = 14.6, 8.5
, 4.0Hz, 1H), 1.78-1.68 (m, 1H), 1.67 (ddd, J = 14.0, 8.0, 4.0Hz, 1H), 1.58-
1.41 (m, 4H), 1.35-1.25 (m, 1H), 1.34 (s, 3H), 1.28 (s, 3H), 1.07 (d, J = 6.5Hz
, 3H), 1.04 (s, 3H), 0.98 (d, J = 7.0Hz, 3H), 0.87 (s, 9H), 0.11 (s, 3H), 0.03
(s, 3H), ¹³ C NMR (100.6MHz, CDCl ₃ ): δ = 215.4, 200.5, 164.6, 154.2, 152.7,
141.7, 118.9, 94.7, 82.3, 76.7, 75.4, 72.2, 61.8, 60.7, 53.4, 49.3, 42.
2, 34.9, 34.1, 33.2, 32.0, 25.9, 23.0, 22.6, 22.1, 20.0, 19.2, 18.1, 15.
9, 14.5, 11.2, -4.4, -4.5.

[0078]

[Chemical 42]

54 mg (0.068 mmol) of aldehyde 20 was treated with 2.5 ml of tBuOH and 2,3-dimethyl-2-butene 2
Dissolve in 0.5 ml, mix with a solution of 30 mg NaClO _{2 and} 30 mg NaH ₂ PO _{4 in} 0.5 ml H ₂ O and stir at room temperature for 45 minutes. To stimulate the reaction mixture, add half saturated NH ₄ Cl solution 2
Mix with 0 ml and extract with methylene chloride (4 x 10 ml). After drying, the solvent is removed and the crude acid 21 (51 mg) thus obtained is used directly in the next reaction.

[0080]

[Chemical 43]

51 mg (0.062 mmol) of the crude acid 21 was dissolved in 1.5 ml of anhydrous THF and at 0 ° C. 57 μl of triethylamine (0.36 mmol) and 43 μl of 2,4,6-trichlorobenzoyl chloride (0.24 mmol)
Mol) and stir at room temperature for 20 minutes. The active ester thus produced was slowly added in liquid form to a solution of 80 mg (0.60 mmol) of DMAP in 35 ml of anhydrous toluene (
Stir for 15 minutes at room temperature (25 ° C.) for 2 hours. The reaction mixture is concentrated by evaporation to about 5 ml and filtered through a short silica gel column (rewash with 30 ml hexane / ethyl acetate). Solvent removal and subsequent column chromatography (hexane / ethyl acetate 4: 1
Yields 18 mg (34%) of the giant lactone 22 as a colorless oil.

Compound 22 (R ³ = TBS, R ⁴ = Troc) ¹ H NMR (600MHz, CDCl ₃ ) δ = 6.99 (s, 1H), 6.56 (s, 1H), 5.21-5.14 (m, 2H), Four.
87 (d, J = 12.0Hz, 1H), 4.75 (d, J = 12Hz, 1H), 4.05 (d, J = 9.8Hz, 1H), 3.30 (dq,
J = 10.2, 6.3Hz, 1H), 2.82 (dd, J = 10.3, 4.0Hz, 1H), 2.79 (dd, J = 16.5, 1.5Hz
, 1H), 2.71 (s, 3H), 2.64 (dd, J = 16.5, 10.0Hz, 1H), 2.25-2.21 (m, 1H), 2.11
(s, 3H), 1.93-1.64 (m, 4H), 1.55-1.42 (m, 2H), 1.32-1.24 (m, 1H), 1.28 (s, 3
H), 1.21 (s, 3H), 1.19 (s, 3H), 1.16-1.08 (m, 1H), 1.12 (d, J = 6.7Hz, 3H), 1.
03 (d, J = 6.7Hz, 3H), 0.88 (s, 9H), 0.16 (s, 3H), -0.03 (s, 3H).

[0083]

[Chemical 44]

18 mg (23 μmol) macrolactone 22 was dissolved in 0.5 ml THF, mixed with 2.5 ml buffered HF-Py (see above) and stirred at room temperature for 72 hours, then Saturates Na
Carefully add to 35 ml of HCO ₃ solution and extract with ether. Removal of solvent (repeated rotary wrapping with toluene) and subsequent column chromatography (hexane / ethyl acetate 2: 1 → 1: 1) yields 5 mg (32%) of the desired product 23 as a colorless oil. At the same time, 6 mg of starting material is recovered. Compound 23 (R ⁴ = Troc)

¹ H NMR (250 MHz, CDCl ₃ ): δ = 6.99 (s, 1H), 6.63 (s, 1H), 5.52 (t, J = 4.5Hz, 1H
), 5.18 (dd, J = 9.0, 2.0Hz, 1H), 4.84 (d, J = 12Hz, 1H), 4.78 (d, J = 12Hz, 1H),
4.15-4.05 (m, 1H), 3.79-3.70 (m, 2H), 3.64-3.52 (m, 1H), 2.87 (t, J = 6.0Hz,
1H), 2.72 (s, 3H), 2.59 (dd, J = 14.0, 10.0Hz, 1H), 2.48 (dd, J = 14.0, 4.0Hz,
1H), 2.35 (t, J = 7.5Hz, 2H), 2.12 (s, 3H), 2.00 (t, J = 5.5Hz, 2H), 1.89-1.81 (
m, 2H), 1.75-1.25 (m, 3H), 1.39 (s, 3H), 1.28 (s, 3H), 1.15 (d, J = 7.0Hz, 3H)
, 1.09 (s, 3H), 0.99 (d, J = 7.0Hz, 3H).

[0086]

[Chemical formula 45]

2.7 mg (4.4 μmol) of 23 was dissolved in 1.5 ml of ethanol and 25 mg of NH ₄ Cl and zinc (
Powder) 25 mg and reflux for 30 minutes. After cooling to room temperature it is filtered through Celite, washed with ethyl acetate and the solvent removed in rotavapor. Subsequent column chromatography (hexane / ethyl acetate 1: 1) gave 1.4 mg (approximately 90%) of 24
Produces (Epothilone B).

Compound 24 (Epothilone B) ¹ H NMR (600 MHz, CDCl ₃ ) δ = 6.97 (s, 1H), 6.60 (s, 1H), 5.41 (d, J = 7.8, 2.4Hz
, 1H), 4.27-4.18 (m, 2H), 3.77 (s, 1H), 3.30 (m, 1H), 2.81 (dd, J = 7.5, 4.5Hz
, 1H), 2.70 (s, 3H), 2.65 (sbr, 1H), 2.54 (dd, J = 14.0, 10.2Hz, 1H), 2.37 (dd
, J = 14.0, 3.0Hz, 1H), 2.13-2.05 (m, 1H), 2.09 (s, 3H), 1.92 (ddd, J = 15.3, 7
.7, 7.7Hz, 1H), 1.78-1.68 (m, 2H), 1.55-1.46 (m, 2H), 1.45-1.33 (m, 2H), 1.
37 (s, 3H), 1.30-1.22 (m, 1H), 1.28 (s, 3H), 1.25 (s, 3H), 1.17 (d, J = 6.7Hz,
3H), 1.08 (s, 3H), 1.01 (d, J = 7.0Hz, 3H).

NMR data can be found in KCNicolaou and A. Mantoulidis (Tet. Lett. 39 (1998) 8633-833.
636). HPLC analysis with a control sample of A. Mantoulidis shows the same material.

Methods of Preparation : All reactions of organometallic agents, and all reactions in anhydrous solvents, are conducted in the absence of air and moisture. The glass equipment used should be in vacuum before the test begins.
It is heated several times (about 0.01 mbar) and aerated with Linde Company dry argon. All reaction batches are magnetically stirred unless otherwise indicated.

Methylene chloride was pre-dried on a basic alumina column of activity stage I (Woelm),
Anhydrous with calcium hydride. After predrying with a basic alumina column on an 8: 1 sodium / potassium alloy, diethyl ether is refluxed until a stable blue coloration of the benzophenone indicator is achieved, which is freshly distilled off before use. Tetrahydrofuran (THF) is pre-dried over KOH, filtered through a column coated with basic alumina, then distilled over potassium with triphenylmethane as an indicator. Hexane (Hex) just before column chromatography in a rotary evaporator
Ethyl acetate (EE) is distilled off after predrying over calcium chloride as in.

Chromatographic method : All reactions were performed on Merck Company silica gel with UV-labeled F _254.
Monitored by thin layer chromatography (TLC) on 60-aluminum foil. As the mobile solvent, a solvent mixture consisting of hexane (Hex) and ethyl acetate (EE) is mostly used. For visualization of non-UV-active substances, anisaldehyde / glacial acetic acid / sulfuric acid (1: 100: 1) has mostly been used as a standard soaking reagent. Preparative column chromatography is performed on Merck silica gel-60 (0.04-0.063 mm, 230-400 mesh) in which a solvent mixture consisting of hexane (Hex) and ethyl acetate (EE) or diisopropyl ether is used as eluent.

For analytical and preparative scales, high pressure liquid chromatographic separation (HPLC)
Knauer Company (pump 64, UV and RI detectors, columns and recorders), Waters / Millipore Company (injection system U6K9
) And Milton-Roy (Integrator CI-10) modular system. For analytical HPLC, in most cases 5 μm nucleos
A Nawell column (4.250 mm) with a il) of 7 μm was used for preparative HPLC.
Or a column (16.250 mm, 32.250 mm or 5 μm nucelosil 50)
64.300 mm) is used.

Dye Reagent Dye Reagent I (FI): For most reducible compounds, 1 g cerium (IV) sulfate in 10 ml concentrated sulfuric acid and 90 ml water gives a deep blue reaction during drying. Dye Reagent II (FII): A 10% ethanolic solution of molybdate phosphoric acid represents another dipping reagent for the detection of unsaturated and reducing compounds. Compared to Dye Reagent I, the molybdate phosphate reagent exhibits a broader color spectrum with virtually the same confidence, especially for some functionalities.

Dye Reagent III (FIII): Anisaldehyde 1 m in 100 ml ethanol and 2 ml concentrated sulfuric acid.
l represents a dye reagent that is extremely sensitive and probably also has the broadest color spectrum. Dye Reagent IV (FIV): Like the anisaldehyde reagent, 1 g vanillin in 100 ml ethanol and 2 ml concentrated sulfuric acid is a very sensitive dye reagent with a broad color spectrum.

Dye Reagent V (FV): 1 g of 2,4-dinitrophenylhydrazine in 25 ml of ethanol, 8 ml of water and 5 ml of concentrated sulfuric acid reacts selectively with aldehydes even when not heated and is somewhat slower with ketones. Represents an excellent dipping reagent that reacts with. Dye Reagent VI (FVI): A 0.5% aqueous solution of potassium permanganate shows groups which can be oxidized by decolorization in which unsaturated, non-aromatic structural units react simultaneously without heating.

Spectroscopy and General Analysis : NMR-Spectroscopy ¹ H-NMR spectra were analyzed on a Bruker Company DRX250 DRX400 spectrometer with the material as a solution in deuterated solvent and tetramethylsilane. Record as internal standard. The spectrum is evaluated according to the first order rule. If the resulting signal multiplicity cannot be accounted for in this way, display on the observed line set. NOE-spectroscopy (nuclear Overhauser effect) is used to determine the stereochemistry.

The following abbreviations are used to characterize the signals: s (doublet), d (doublet), dd (doublet).
Heavy line), ddd (6-line system with two identical coupling constants or 8-of three different coupling constants)
Line system), t (triple line), q (quad line), quint (quint line), sext (6 line), sept (7 line), m (multiline), mc (multiline center) ), Br (broad), hv (semi-latent signal) and v (latent signal)
. ¹³ C NMR spectra are measured as internal standard with a Bruker AC250 with a CDCl ₃ signal at 77.0 ppm where the proton resonance spans broadband coupling.

IR-Spectroscopy Infrared spectra were analyzed using the Perkin-Elmer Company instrument (model 257 or 580B) and Nicolet Company (FTIR-interferometer system).
55XC). The oil is measured as a film between potassium bromide disks. Display the bands as the wave number (cm ^-1 ) decreases. The following symbols are selected for characterization: vs (very strong), s (strong), m (middle), w (weak).

Abbreviations: abs .: anhydrous, Ar: aryl / aromatic, cld.:calculated, Brine (brine
): Cold saturated normal salt solution, nBuLi: n-butyllithium, c: concentration, COSY: correlation spectroscopy (correlation spectroscopy), CSA: camphorsulfonic acid, TLC: thin layer chromatography, DCM: dichloromethane, DDQ: dichloro-dicyano-quinone, de: diastereomeric excess, DIBAH: diisobutyl-aluminum hydride, DIPA: diisopropylamine, DMAP: dimethylaminopyridine, DMF: N, N'-dimethylformamide, DMS: dimethyl sulfide, DMSO : Dimethyl sulfoxide, ds: diastereoselection, EA: elemental analysis,

Ee: Enantiomeric excess, EE: Ethyl acetate, EI: Electron impact ionization, eq: Equivalent (
Multiple), eV: electron volt, FG: functional group, FI: field ionization, gef .: found, ges .: saturated, h: time (multiple), Hex .: n-hexane, HMDS: Hexamethyldisilazide, HPLC: High pressure liquid chromatography, HunigBase: N-ethyl-diisopropylamine, HRMS: High resolution mass spectrometry, HV: High vacuum, iPrOH: 2-Propanol, IR
: Infrared analysis method / infrared spectrum, J: coupling constant, LDA: lithium diisopropylamine, Lsq .: solution, Lsm .: solvent, MC: methylene chloride, Me: methyl, MeLi: methyllithium, min .: min ( , Including multiple), MS: mass spectrometry / mass spectrum,

NMR: nuclear magnetic resonance, NOE: nuclear Overhauser effect, PCC: pyridinium chlorochromate, PG: protecting group, Ph: phenyl, ppm: parts permillion, Rkt .: reaction, rt .: residence time, RT : Room temperature (20 to 30 ° C), Std .: time (including plural), TBAF: tetra-n-butylammonium fluoride, TBDPS: t-butyldiphenyl-silyl chloride, TBDPSCl: t-butyldiphenyl-silyl chloride, TBS: t-butyldimethyl-silyl chloride,
TBSCl: t-butyldimethyl-silyl chloride, TBSTriflate: t-butyldimethyl-silyl-triflate, TEA: triethylamine, tert / t: third, TFA: trifluoroethanoic acid, TFAA: trifluoroethanoic anhydride, TFMS: Trifluoromethanesulfonic acid, THF: tetrahydrofuran, TMS: trimethylsilyl-, u: g · mol ⁻¹ .

The preceding examples reproduce similar success by substituting the general or specially described reactants and / or operating conditions of the present invention for those used in the preceding examples. You can From the foregoing description, those skilled in the art can easily confirm the essential characteristics of the present invention, and various changes and modifications of the present invention can be made without departing from the spirit and scope thereof. Can be applied to the usage and conditions.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW F-term (reference) 4C063 AA01 BB03 CC71 DD62 EE05                 4C071 AA01 BB01 CC12 EE02 FF18                       GG01 GG05 HH05 HH09 JJ10                       KK01 LL01                 4H049 VN01 VP01 VR23 VR41 VW01

Claims (7)

[Claims] 1. A method for producing an epothilone compound, comprising the following formula II: (Where PG is a protecting group) an improved process comprising cyclizing a compound formed from an intermediate thereof to produce the above compound. 2. The method according to claim 1, wherein PG is a TBS or TES group. 3. A compound of formula II wherein T as a PG is converted to a TES group during the process.
The method of claim 1 containing a BS group. 4. The cyclization reaction is represented by Formula 21: The method according to claim 1, which is a reaction of the compound of 5. A compound of formula 21 is a compound of formula 11: To form an aldehyde, which can be converted to the compound: Combined with Equation 12: To produce the enoyl sultam of and reacting this enoyl sultam 12 with L-selectride: Formulas 13 and 14: To produce the compound of Sultam 13 to reduce aldehyde 15: This aldehyde 15 is converted to ketone 16: By reacting with compound 17: To protect the 17-OH group of compound 17 to form alkene 18: And alkene 18 is dehydroxylated and glycosylated to give aldehyde 19: And deprotecting the 15-position of aldehyde 19 to give aldehyde 20: Compound 21: embedded image was obtained by subjecting aldehyde 20 to oxidation and macrolactonization. Wherein each PG is independently a protecting group, and is The method of claim 4, wherein: 6. A compound of formula 21 is cyclized to form formula 22: Of the formula 23: embedded image by deprotecting the 3-position oxygen atom. 5. The method of claim 4, comprising forming the compound of claim 1 and removing the protecting group at the 7-position to form epothilone B. 7. The following formulas 5 to 21: [Chemical 18] (In the formula, PG is a protecting group, and And R is Bn or PMB).