JPH0616689A - De-n-acetyl gm2 - Google Patents

Abstract

PURPOSE:To provide a new compound having antigenicity and useful for the production of a monoclonal antibody to be used in the diagnosis of cancer and melanoma. CONSTITUTION:The de-N-acetyl GM2 of formula I (Ac is acetyl) and its salt. The compound can be produced by reacting a compound of formula II (R is Li; Piv is pivaloyl; Bz is benzoyl) with methylamine in methanol. The compound of formula II is a new compound and obtained e.g. by subjecting a compound of formula III successively to N-phthaloylation and acetylation, reacting with a compound of formula IV (Bn is benzyl), reacting the product with a compound of formula V (Et is ethyl) and then with thioacetic acid, subjecting the product successively to debenzylation and acetylation, reacting with hydrazineacetic acid, reacting the product with trichloroacetonitrile, reacting the obtained compound with a compound of formula VI and finally reacting the product with lithium iodide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to gangliosides, and more particularly to de-N-acetyl-GM ₂ .

[0002]

2. Description of the Related Art In recent years, gangliosides from which the N-acetyl group of sialic acid has been eliminated, that is, de-N-acetylgangliosides, have been found in nature and have attracted attention as cancer-related antigens (N. Hanai, et at ., J. Biol. Chem., 263, 6
296-6301, 1988; AE Manzi, et al., J. Biol. Che
m., 265, 13091-13103, 1990). Hakomori et al. Semi-synthesize de-N-acetyl GM ₃ by partially cleaving the amide bond using GM ₃ obtained from nature as a starting material, but the amount of naturally occurring de-N-acetyl ganglioside is very small. Therefore, it was not possible to use a large amount of GM ₃ as a raw material. With the discovery of such modified gangliosides, the biological function of other de-N-acetyl gangliosides has been attracting attention. The inventors of the present invention have conducted research for the purpose of providing de-N-acetyl GM ₂ , but GM ₂ is a ganglioside that is present only in a trace amount in the natural world and is not suitable for use as a raw material for production. Two N- in
Because it has an acetyl group and one amide bond, to produce semi-synthetically de -N- acetyl -GM ₂ from GM ₂ it is necessary to perform the cutting of these amide bonds selectively Yes, the manufacturing process is complicated.

[0003]

SUMMARY OF THE INVENTION Accordingly, the object of the present invention is to provide de-N-acetyl-GM ₂ by a synthetic method. Also, de-N-
It is also an object to provide a production intermediate useful for the production of acetyl-GM ₂ . The de-N-acetyl GM ₂ of the present invention is represented by the following formula.

[0004]

[Chemical 6]

Salts of the above compounds are also included in the present invention. Examples of the base addition salt include lithium salt, sodium salt, potassium salt, ammonium salt and the like of the above compound, and acid addition salt includes hydrochloride, sulfate, phosphate, malate, tartaric acid of the above compound. Examples thereof include salts and oxalates. The present invention also provides a production intermediate useful for producing the above-mentioned de-N-acetyl-GM ₂ . The intermediate for producing de-N-acetyl-GM ₂ of the present invention is a compound represented by the following general formula (II):

[0006]

[Chemical 7]

A compound represented by the following general formula (III):

[0008]

[Chemical 8]

A compound represented by the following general formula (IV):

[0010]

[Chemical 9]

[0011] In the above general formula, R ¹ , R ⁴ , R ⁸
Represents an amino group or a protected amino group. Examples of the protected amino group include an amino group protected by a protecting group known to those skilled in the art as a protecting group for an amino group such as an acetyl group, a phthaloyl group and a 1,2-cyclohexanedicarboxylimide group. R ² , R ⁵ , and R ⁹ represent a hydrogen atom or a lower alkyl group, and the lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, Isopropyl group,
Examples thereof include a butyl group and a tertiary butyl group. X is a hydroxyl group, a hydroxyl group having a protective group, a halogen atom, -OCNHCCl ₃ , or a group represented by the following formula:

[0012]

[Chemical 10]

(In the formula, R ³ is a hydrogen atom or a hydroxyl-protecting group). Protecting group for hydroxyl group contained in X or R
^The hydroxyl-protecting group represented by ³ may be any protecting group known to those skilled in the art as a hydroxyl-protecting group such as an acetyl group, a benzyl group and a benzoyl group. The halogen atom is preferably a chlorine atom or a fluorine atom.
Ac represents an acetyl group and Piv represents a pivaloyl group. R ⁶ and R ¹¹ independently represent a hydroxyl-protecting group, and as the hydroxyl-protecting group, any protecting group known to those skilled in the art as a hydroxyl-protecting group such as acetyl group, benzyl group and benzoyl group may be used. You can R ⁷ represents an amino group, a protected amino group, or an azido group, and the protected amino group is protected with a protecting group known to those skilled in the art as a protecting group for amino groups such as acetyl group and phthaloyl group. An amino group may be mentioned. R ¹⁰ represents a hydrogen atom or a protective group for a hydroxyl group such as an acetyl group.

Among the above-mentioned production intermediates of the present invention, preferred compounds are used to produce the ganglioside compound de-N- of the present invention.
An example of the method for producing acetyl-GM ₂ is shown in the following synthetic scheme. In the scheme, Me is a methyl group, Ac is an acetyl group, Phth is a phthaloyl group, Bn is a benzyl group, Piv is a pivaloyl group, Et is an ethyl group, and Bz is a benzoyl group. Compound 1 is described in JP-A-3-279395, and compound 4 is disclosed in Journal of American Chemical Society (J. Am. Chem. Soc., 111 (22), 8508-8510, 1
989)) and Carbohydrate Research (Carbohydr.
Res., 203, 205-217, 1990), compound 10 is a synet
(Synlett, 445-448, 1990), and Compound 22 is Carbohydrate Research (Carbohydr. Res., 158, 113-123,
1986).

[0015]

[Chemical 11]

[0016]

[Chemical 12]

[0017]

[Chemical 13]

[0018]

[Chemical 14]

As the reaction conditions of the reaction shown in the above scheme, the conditions shown in Table 1 below can be exemplified.
In the table, DMAP is dimethylaminopyridine, TMSOTf is trimethylsilyltrifluoromethanesulfonate, DMTST is dimethyl (methylthio) sulfonium trifluoromethanesulfonate, NIS is N-iodosuccinimide, THF.
Is tetrahydrofuran, DMF is N, N-dimethylformamide, and DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene.

[0020]

[Table 1] Reaction conditions ──────────────────────────────────── Compound No. Reaction reagent or Catalyst Solvent temperature Time ───────────────────────────────────── 1 References of known substances ── ────────────────────────────────── Reagent Catalyst A Et ₃ N, such as MeOH , EtOH, 0 ℃ -50 ° C 1-10 days 1- N-phthal tertiary amines PrOH, H ₂ O 24 ° C 5 days Roylation B tertiary amines Reagent A: phthalic anhydride Reagent B: orthomeoxycarbonyl C Na ₂ CO ₃ Benzoyl chloride NaHCO ₃ reagent C: N-carboethoxyphthalic acid KHCO ₃ imide K ₂ CO ₃ ─────────────────────────────── ────── Reagent Catalyst 2 Ac ₂ O Pyridine such as pyridine , 0 ℃ to 50 ℃ 1 ~ 48 hours (the above reaction tertiary amines THF, CH ₂ Cl _2, 24 ° C 20 hours intermediate (CH ₂ Cl) ₂ acetyl DMAP) AcCl tertiary amines ──────────── ───────────────────────── CH ₂ N ₂ MeOH , EtOH 0 ° C to 30 ° C 0.5 to 2 hours 3 CH ₃ I NaOH 24 ° C MeOH Acid Catalyst ──────────────────────────────────── 4 Known substances References ──────── ──────────────────────────── Catalyst EtCN , MeCN, PhCN -90 ℃ to 0 ℃ 1 to 24 hours AgOTf and PhseCl PrCH, CH ₂ Cl ₂ , -50 ℃ 8 hours 5 , 6 , 〃 and TMSOTf (ClCH ₂ ) ₂ , PhCH ₃ , 7 DMTST, NIS and TfOH THF, Et ₂ O, C ₆ H ₆ , MeOTf, MeSOTf and CCl ₄ , CHCl ₃ , CuBr ₂ , AgOTf and MeNO ₂ nBu ₄ NBr ──────────────────────────────────── 8 , 9, 2 sweat Le of acetyl 1 to 48 hours acetylation 2 of 2 and the same as the same le of the same 17 hours ─────────────────────────── ───────── 10 References to known substances ───────────────────────────────────── 11 , 12 5 , 6 , 7 Same as 7 , 5 , 6 , 7 -90 ℃ to 0 ℃ Same as 2 to 48 hours -78 ℃ to 20 ℃ 19 hours ──────────────── ───────────────────── Reaction reagents and catalysts AcSH 0 ° C to 50 ° C 1 to 10 days AcSH CH ₂ Cl ₂ , CHCl ₃ , 24 ° C 3 days H ₂ And Pd-C, (ClCH ₂ ) ₂ , CHCl ₃ , 13 H ₂ and Pd (OH) ₂ -C THF, Et ₂ O, PhCH ₃ , H ₂ and Pt ₂ OC ₆ H ₆ ,, AcOEt, CCl ₄ H ₂ O- and Ph ₃ PH ₂ S reaction reagents other than AcSH are N-acetylated after reduction ────────────────────────────── ──────── 13 Reaction reagent Catalyst M eOH , EtOH, PrOH 20 ℃ ~ 40 ℃ 5 ~ 80 hours Debenben H ₂ Pd (OH ₂ ) -C AcOEt 24 ℃ 48 hours Zylation Pd-C D Pd-C D: Cyclohexane E Pd-C E: 1, 3-cyclohexadiene ──────────────────────────────────── 14 , 15 , 2 acetyl 2 acetyl Acetyl of 2 ~ 1 to 5 days 16 and 17 Same as same as same as same as 3 days (acetylation of the above compound) ─────────────────────── ────────────── 18, 19 reagent DMF 40 ℃ ~80 ℃ 5 ~90 min _{H 2 NNH 2 · AcOH, 65} ℃ 30 minutes piperidine acetate ──────── ──────────────────────────── 20 , 21 Reaction reagent Catalyst (ClCH ₂ ) ₂ -20 ℃ to 40 ℃ 1 to 24 hours Cl ₃ CCN DBU CH ₂ Cl ₂ , CHCl ₃ , 0 ℃ 3 hours NaH, LiH, CCl ₄ , THF, K ₂ CO ₃ PhCH ₃ , C ₆ H ₆ ─────────────── ─── ────────────────── 22 known substance literature reference ─────────────────────────── ───────── Catalyst CHCl ₃ , CH ₂ Cl ₂ , -80 ℃ to 40 ℃ 1 to 24 hours 23 , 24 BF ₃ OEt ₂ , TMSOTf (ClCH ₂ ) ₂ , PhCH ₃ , -18 ℃ ～ 0 ℃ 3 hours PPTS, CCl ₃ CHO C ₆ H ₆ , THF, Et ₂ O, CCl ₄ ──────────────────────────── ────────── Reaction reagent pyridine , 50 ℃ ~ 130 ℃ 0.5 ~ 6 hours 25 , 26 LiI , NaI, KI Collidine, 110 ℃ 2 hours picoline ───────────── ──────────────────────── Reaction reagent Primary alkylamine Alcohol A method: MeNH ₂ A method: MeOH A method: 0 ℃ to 50 ℃ 5 100 hours 24 ° C. 50 h 27 B method: MeNHNH ₂ B method: EtOH B method: 24 ° C. to 90 ° C. 5 to 100 hours 75 ° C. 48 hours PhNHNH ₂ and tertiary amines ───────── ────────────────────────── (Note) In the table, the underlined reagents, catalysts, solvents, temperature, and reaction time are Indicates the response condition.

[0021]

INDUSTRIAL APPLICABILITY The ganglioside compound de-N-acetyl-GM ₂ provided by the present invention is useful because it has various physiological actions such as antigenicity. For example, a monoclonal antibody can be prepared using the compound of the present invention, and the monoclonal antibody can be used for diagnosis of cancer, melanoma and the like. Further, by utilizing the production intermediate of the present invention, the ganglioside compound de-N-acetyl-
GM ₂ is manufactured efficiently.

[0022]

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0023]

Example 1 Synthesis of Compound 2 Compound 1 (297 mg, 1.0 mmol), phthalic anhydride (1.777)
g, 12.0 mmol) and triethylamine (2.17 ml, 15.4
mmol) in methanol (10 ml) at room temperature for 5 days. The reaction solution was evaporated to dryness under reduced pressure, and pyridine (10 ml), acetic anhydride (10 ml) and dimethylaminopyridine (122 mg,
(1.0 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with 0.1N-HCl and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (Wako Gel C-300, 9: 1 CHCl ₃ -methanol) to obtain compound 2 (474 mg, 79.7%).

[Α] _D + 73.2 ° (in c 1.0 CHCl ₃ );
R _F 0.40 4: 1 CHCl ₃ in ¹ Hn.mr data in methanol: δ _H (CDCl ₃ ) 7.835 (m, 2H, aromatic hydrogen), 7.727 (m, 2H, aromatic hydrogen), 5.609 (dt, 1H, J = 5.0
And 10.9 Hz, H-4), 5.478 (ddd, 1H, J = 3.0, 5.2 and
8.5 Hz, H-8), 5.195 (dd, 1H, J = 1.8 and 8.4 Hz, H-
7), 4.983 (dd, 1H, J = 1.8 and 10.6 Hz, H-6), 4.299 (d
d, 1H, J = 4.0 and 12.5 Hz, H-9), 4.240 (t, 1H, J = 10.
6 Hz, H-5), 4.084 (dd, 1H, J = 5.1 and 12.5 Hz, H-9 '),
2.963 (dd, 1H, J = 4.9 and 12.7 Hz, H-3eq), 2.238, 2.
163, 2.146, 1.945 and 1.844 (5s, 15H, 4 OAc and SMe),
And 2.003 (t, 1H, J = 12.1Hz, H-3ax).

[0025]

Example 2 Synthesis of Compound 3 Compound 2 (41.9 mg, 70.4 μmol) was dissolved in methanol (3 ml), and an ether solution of diazomethane was added at room temperature to the starting material 2.
Was added until disappeared on TLC. The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to flash chromatography (C-300, 4 g,
93: 7 CHCl ₃ -THF) and the compound 3 (38.9 mg,
90.7%). ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.825 (m, 2H, aromatic hydrogen), 7.731 (m, 2H, aromatic hydrogen), 5.501 (dt, 1H, J =
5.1 and 10.6 Hz H-4), 5.454 (ddd, 1H, H = 2.6, 4.8
And 9.1 Hz, H-8), 5.172 (dd, 1H, J = 2.2 and 8.8
Hz, H-7), 4.873 (dd, 1H, J = 2.2 and 10.6 Hz, H-6),
4.239 (dd, 1H, J = 2.6 and 12.5 Hz, H-9), 4.218 (t,
1H, H = 10.6 Hz, H-5), 3.889 (s, 3H, OMe), 2.905 (dd,
1H, J = 5.1 and 12.8 Hz, H-3eq), 2.195, 2.169, 2.15
1, 1.926 and 1.839 (5s, 15H, 4.0Ac and SMe), and
1.988 (dd, 1H, H = 11.5 and 12.6 Hz, H-3ax). [Α] _D + 75.2 ° Rf 0.49 9: 1 CHCl ₃ -THF Elemental analysis C ₂₇ H ₃₁ NO ₁₃ S Calculated value: C, 53.20; H,
5.13; N, 2.30 Found: C, 53.67; H, 5.16; N, 2.12

[0026]

Example 3 Synthesis of Compounds 5 , 6 and 7 Compound 3 (30.7 mg, 50.4 μmol) and Compound 4 (87.5 mg, 10
9.5 μmol) and EtCN (1.4 ml) in the presence of Ms 4A (0.10 g).
The mixture was stirred at room temperature for 3 hours. After cooling the reaction mixture to −50 ° C., it was mixed with AgOTf (29.9 mg, 115.2 μmol) EtCN (0.4 m
l) solution was added, and PhSeCl (21.4 mg, 109.5 μmol) E was added.
A tCN (0.4 ml) solution was added, and the mixture was stirred at the same temperature for 8 hours.
The reaction mixture was diluted with chloroform (100 ml), filtered through Celite, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate (50 ml). The washings were re-extracted with chloroform (50 ml), the chloroform layers were combined and washed with saturated saline (100 ml). Solvent is anhydrous MgSO
After drying at _4, it was dried under reduced pressure. Sephadex LH-2 residue
Gel filtration with 0 (130 ml, methanol) followed by HPLC (GL
Science, Inert sil PREP-SIL, 20 x 250mm, CHCl
₃ -THF 93: 7, 16 ml / min, UV 260 nm),
Compound 5 (34.1mg, 47.1%) Compound 6 (5.4mg, 7.5%)
And compound 7 (11.3 mg, 39.9%) were obtained. 5 [α] _D + 15.4 ° (c 1.0, CHCl ₃ ) 6 [α] _D −3.7 ° (c 1.0, CHCl ₃ ) Rf 0.23 19: 1 CHCl _{3 −} THF in Rf 0.34 19: 1 CHCl _{3 −} THF Elemental analysis C ₇₈ H ₈₇ NO ₂₅ Elemental analysis C ₇₈ H ₈₇ NO ₂₅ Calculated value: C, 65.13; H, 6.10; N, 0.97 Calculated value: C, 65.13; H, 6.10; N, 0.97 Measured value: C, 65.00; H, 6.12; N, 0.91 Actual value: C, 65.00; H, 6.21; N, 0.96 7 [α] _D + 80.4 ° (c 1.0, CHCl ₃ ) Rf 0.31 19: 1 CHCl ₃ −THF Medium element Analysis C ₂₆ H ₂₇ NO ₁₃ Calculated: C, 55.62; H, 4.85; N, 2.49 Measured: C, 5
6.04; H, 4.94; N, 2.55 Compound 5 ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.821 (m, 2H, aromatic hydrogen), 7.730 (m, 2H, aromatic hydrogen), 5.495 (m, 2H, H = 4
c and H-8c), 5.161 (dd, 1H, J = 2.6 and 8.6Hz, H-7
c), 5.124 (dd, 1H, J = 7.7 and 9.2 Hz, H-2a), 5.026
(dd, 1H, J = 2.6 and 10.6 Hz, H-6c), 4.575 (d, 1H, J =
7.7 Hz, H-1b), 4.448 (d, 1H, J = 8.1 Hz, H-1a), 4.188
(dd, 1H, J = 3.7 and 12.5 Hz, H-9c), 4.183 (t, 1H,
J = 10.6 Hz, H-5c), 4.143 (dd, 1H, J = 3.3 and 9.5 H
z, H-3b), 4.082 (t, 1H, J = 8.8 Hz, H-4a), 3.937 (dd,
1H, J = 5.5 and 12.5 Hz, H-9'c), 3.847 (s, 3H, OMe),
3.829 (br.s, 1H, H-4b), 3.632 (t, 1H, J = 8.8 Hz, H-3
a), 3.359 (dd, 1H, J = 7.7 and 9.2 Hz, H-2b), 2.721
(dd, 1H, J = 5.1 and 12.8 Hz, H-3ceq), 2.099,1.92
9, 1.900 and 1.879 (4s. 12H, 4OAc), 1.987 (t, 1H,
J = 12.5 Hz, H-3cax), and 1.130 (s, 9H, (CH ₃ ) ₃ C). Compound 6 ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.827 (m, 2H, aromatic hydrogen), 7.727 (m, 2H, aromatic hydrogen), 5.970 (dt, 1H, J =
5.1 and 11.4 Hz, H-4c), 5.446 (dd, 1H, J = 2.6 and 10.6 Hz, H-6c), 5.280 (td, 1H, J = 2.9 and 8.4 H
z, H-8c), 5.227 (t, 1H, J = 2.6 Hz, H-7c), 5.109 (dd,
1H, J = 8.1 and 9.2 Hz, H-2a), 4.888 (dd, 1H, J = 2.6
And 12.5 Hz, H-9c), 4.472 (d, 1H, J = 7.7 Hz, H-1b),
4.427 (d, 1H, J = 8.1 Hz, H-1a), 4.233 (t, 1H, J = 10.6
Hz, H-5c), 4.050 (m, 2H, H-4a and H-9'c), 3.618 (t,
1H, J = 8.8 Hz, H-3a), 3.484 (s, 3H, OMe), 3.364 (dd
d, 1H, J = 2.2, 4.0 and 9.9 Hz, H-5a), 2.794 (dd, 1
H, J = 5.1 and 13.2 Hz, H-3ceq), 2.093, 1.892, 1.86
6, and 1.836 (4s, 12H, 4OAc), 1.899 (t, 1H, J = 12.5H
z, H-3cax), and 1.129 (s, 9H, (CH ₃ ) ₃ C). Compound 7 ¹ Hn. mr Data: δH (CDCl ₃ ) 7.855 (d, 1H, J = 5.
5 Hz, aromatic hydrogen), 7.845 (d, 1H, J = 5.5 Hz, aromatic hydrogen), 7.751 (d, 1H, J = 5.5 Hz, aromatic hydrogen), 7.745 (d,
1H, J = 5.5 Hz, aromatic hydrogen), 6.139 (dd, 1H, J = 2.6 and 9.2 Hz, H-4), 6.003 (d, 1H, J = 2.6 Hz, H-3), 5.424
(dt, 1H, J = 2.6 and 6.2 Hz, H-8), 5.252 (dd, 1H, J =
2.2 and 11.4 Hz, H-6), 5.252 (dd, 1H, J = 2.0 and
7.0 Hz, H-7), 4.541 (dd, 1H, J = 9.2 and 11.4 Hz, H
-5), 4.500 (dd, 1H, J = 2.9 and 12.5 Hz, H-9), 4.116
(dd, 1H, J = 6.2 and 12.5 Hz, H-9 '), 3.830 (s, 3H, O
Me), 2.096, 2.046, 1.964 and 1.930 (4s, 12H, 4OA
c).

[0027]

Example 4 Synthesis of Compound 8 Compound 5 (15.2 mg, 0.01 mmol) and dimethylaminopyridine (3.0 mg, 0.024 mmol) were dissolved in pyridine (0.2 ml), acetic anhydride (50 μl) was added thereto, and the mixture was stirred at room temperature. It was stirred for 17 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to gel filtration (Sephadex LH-20, 17 ml, methanol), followed by flash chromatography (C-300, 1.8 g, 24: 1 CHCl _3).
-THF) to obtain Compound 8 (11.8 mg, 75.6%). [Α] _D + 17.0 ° (c 0.58, CHCl ₃ ) Rf 0.40 19: 1 CHCl ₃ -THF Elemental analysis C ₈₀ H ₈₉ NO ₂₆ Calculated value: C, 64.90; H, 6.06;
N, 0.95 Found: C, 64.40; H, 6.18; N, 0.99 ¹ Hn. Mr Data: δH (CDCl ₃ ) 5.666 (ddd, 1H, J =
2.6, 4.4 and 9.2 Hz, H-8c), 5.576 (dt, 1H, J = 5.1
And 11.4 Hz, H-4c), 5.177 (dd, 1H, J = 2.6 and 9.2
Hz, H-7c), 5.116 (dd, 1H, J = 8.4 and 9.2 Hz, H-2
a), 5.102 (br. d, 1H, J = 3.3 Hz, H-4b), 4.761 (dd, 1
H, J = 3.3 and 11.0 Hz, H-6c), 4.761 (d, 1H, J = 7.7
Hz, H-1b), 4.618 (dd, 1H, J = 3.3 and 9.9 Hz, H-3
b), 4.425 (d, 1H, J = 8.1 Hz, H-1a), 4.182 (t, 1H, J = 1
0.6 Hz, H-5c), 4.165 (dd, 1H, J = 2.6 and 12.5 Hz, H-
9c, 4.094 (t, 1H, J = 9.2 Hz, H-4a), 3.963 (dd, 1H, J =
4.8 and 12.8 Hz, H-9'c), 3.928 (s, 3H, OMe), 3.795
(dd, 1H, J = 1.8 and 11.0Hz, H-6a), 3.628 (t, 1H, J
= 9.2 Hz, H-3a), 3.465 (dd, 1H, J = 7.7 and 9.5 Hz,
H-2b), 3.400 (ddd, 1H, J = 1.5, 4.8 and 9.5 Hz, H-5
a), 2.742 (dd, 1H, J = 5.1 and 12.5 Hz, H-3ceq), 2.
093, 2.002, 1.858, 1.828 and 1.815 (5s, 15H, 50A
c), 1.790 (t, 1H, J = 12.1 Hz, H-3cax), and 1.132
(s, 9H, (CH ₃ ) ₃ C).

[0028]

Example 5 Synthesis of Compound 9 Compound 6 (6.9 mg) was converted into compound 9 (6.7 mg, 94.4%) by the same method as for the synthesis of compound 8 . [Α] _D + 6.1 ° (c 0.35, CHCl ₃ ) Rf 0.47 19: 1 CHCl ₃ -THF Elemental analysis C ₈₀ H ₈₉ NO ₂₆ Calculated value: C, 64.90; H, 6.06;
N, 0.95 Found: C, 64.48; H, 6.21; N, 1.02 ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.805 (m, 2H, aromatic hydrogen), 7.703 (m, 2H, aromatic hydrogen), 5.835 (dt, 1H, J =
4.8 and 11.0 Hz, H-4c), 5.585 (td, 1H, J = 2.2 and 9.5 Hz, H-8c), 5.300 (dd, 1H, J = 2.2 and 12.5 H
z, H-9c), 5.295 (d, 1H, J = 3.7 Hz, H-4b), 5.268 (t, 1
H, J = 2.2 Hz, H-7c), 5.122 (dd, 1H, J = 8.1 and 9.2 H
z, H-2a), 5.058 (dd, 1H, J = 2.6 and 10.6 Hz, H-6c),
4.525 (d, 1H, J = 7.7 Hz, H-1b), 4.432 (d, 1H, J = 8.1
Hz, H-1a), 4.271 (dd, 1H, J = 3.7 and 9.9 Hz, H-3b),
4.155 (t, 1H, J = 10.6 Hz, H-5c), 3.878 (dd, 1H, J = 9.
5 and 12.1 Hz, H-9'c), 3.838 (dd, 1H, J = 4.0 and 7.
0 Hz, H-5b), 3.750 (dd, 1H, J = 2.2 and 11.0 Hz, H-6
a), 3.698 (dd, 1H, J = 5.1 and 11.0 Hz, H-6'a), 3.653
(dd, 1H, J = 7.7 and 9.9 Hz, H-2b), 3.642 (t, 1H, J =
9.0 Hz, H-3a), 3.478 (dd, 1H, J = 4.0 and 10.6 Hz,
H-6b), 3.390 (ddd, 1H, J = 1.8, 4.8 and 9.5Hz, H-5
a), 3.355 (s, 3H, OMe), 3.247 (dd, 1H, J = 7.0 and 1
0.5 Hz, H-6'b), 2.806 (dd, 1H, J = 5.1 and 13.6 H
z, H-3ceq), 2.277, 2.105, 1.909, 1.850, and 1.800
(5s, 15H, 5OAc), 1.930 (dd, 1H, J = 11.4 and 13.6 H
z, H-3cax), and 1.126 (s, 9H, (CH 3) 3 C).

[0029]

Example 6 Synthesis of Compounds 11 and 12 Compound 5 (46.1 mg), 32 μmol) and Compound 10 (142.3
mg, 245 μmol) in the presence of MS 4A (0.46 g), EtCN (1.5 ml)
The mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to −78 ° C. and a solution of AgOTf (101.5 mg, 391 μmol) in EtCN (0.7 ml) was added, followed by PhSeCl (73.0 mg, 374 μmol) in EtCN.
(0.8 ml) solution was added and stirred at the same temperature for 3 hours.
The mixture was stirred at 20 ° C for 16 hours. Chloroform the reaction mixture (60 ml)
It was diluted with and filtered through Celite. The filtrate was saturated with aqueous sodium hydrogen carbonate (30 m
l), wash the solution with chloroform (30 ml),
The chloroform layers were combined and washed with saturated brine (70 ml). The solvent was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to gel filtration (Sephadex LH-20, 260 ml,
(Methanol) purification, followed by flash chromatography (Wako Gel C-300, 6 g, 4: 1 toluene-AcOEt) to give compound 11 (48.2 mg, 79.3%) and compound 12 (8.5
mg, 14.0%) was obtained. Compound 11 Compound 12 (α) _D + 3.5 ° (c 0.98, CHCl ₃ ) (α) _D + 27.7 ° (c 0.91, CHCl ₃ ) Rf 0.34 3: 1 in toluene-AcOEt Rf 0.40 3: 1 toluene-AcOEt Elemental analysis C ₁₀₅ H ₁₁₄ N ₄ O ₂₉ : Elemental analysis C ₁₀₅ H ₁₁₄ N ₄ O ₂₉ : Calculated value: C, 66.51; H, 6.06; N, 2.95 Calculated value: C, 66.51; H, 6.06; N, 2.95 Found: C, 65.89; H, 6.10; N, 2.95 Found: C, 66.72; H, 6.11; N, 3.04 Compound 11 ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.830 (m, 2H, aromatic Hydrogen), 7.731 (m, 2H, aromatic hydrogen), 5.430 (ddd, 1H, J
= 5.1, 10.6 and 11.7 Hz, H-4c), 5.344 (ddd, 1H, J = 2.
5, 4.0 and 9.5 Hz, H-8c), 5.121 (dd, 1H, J = 1.8
And 9.3 Hz, H-7c), 5.047 (dd, 1H, J = 8.1 and 9.5
Hz, H-2a), 4.656 (d, 1H, J = 8.1 Hz, H-1b), 4.474 (d,
1H, J = 7.7 Hz, H-1d), 4.429 (d, 1H, J = 8.1 Hz, H-1
a), 4.174 (dd, 1H, J = 2.9 and 12.8 Hz, H-9c), 4.11
5 (t, 1H, J = 10.3 Hz, H-5c), 3.955 (dd, 1H, J = 4.0
And 12.8 Hz, H-9'c), 3.894 (dd, 1H, J = 8.1 and 1
0.6Hz, H-2b), 3.840 (dd, 1H, J = 7.7 and 9.5 Hz, H-
2d), 3.768 (d, 1H, J = 3.3 Hz, H-4b), 3.739 (s, 3H, OM
e), 3.577 (t, 1H, J = 8.8 Hz, H-3a), 3.369 (dd, 1H, J
= 2.6 and 10.6 Hz, H-3b), 2.580 (dd, 1H, J = 5.1
And 13.6 Hz, H-3ceq), 2.086 (dd, 1H, J = 12.0 and 1
3.6 Hz, H-3cax), 2.068, 1.912, 1.836 and 1.776 (4
s, 12H, 4OAc), and 1.195 (s, 9H, (CH ₃ ) ₃ C). Compound 12 ¹ Hn. mr Data: δH (CDCl ₃ ) 7.811 (m, 2H, aromatic hydrogen), 7.726 (m, 2H, aromatic hydrogen), 5.685 (ddd, 1H, J
= 2.6, 4.4 and 9.2 Hz, H-8c), 5.506 (ddd, 1H, J = 5.
1, 11.7 and 13.5 Hz, H-4c), 5.194 (dd, 1H, J = 2.6
And 9.2 Hz, H-7c), 5.104 (dd, 1H, J = 7.7 and 9.5
Hz, H-2a), 4.926 (d, 1H, J = 3.3 Hz, H-1d), 4.860 (dd,
1H, J = 2.6 and 10.6 Hz, H-6c), 4.793 (d, 1H, J = 7.3
Hz, H-1d), 4.412 (d, 1H, J = 8.1 Hz, H-1a), 4.224 (t,
1H, J = 10.6 Hz, H-5c), 4.125 (dd, 1H, J = 2.6 and 1
2.8 Hz, H-9c), 4.073 (br.s, 1H, H-4d), 3.978 (t, 1
H, J = 9.9 Hz, H-4a), 3.981 (dd, 1H, J = 4.8 and 12.5
Hz, H-9′c), 3.737 (s, 3H, OMe), 3.681 (d, 1H, J = 2.
2 Hz, H-4b), 3.554 (dd, 1H, J = 7.3 and 10.6 Hz, H-2
d), 2.844 (dd, 1H, J = 4.8 and 11.8 Hz, H-3ceq), 2.
114, 1.875, 1.826 and 1.565 (4s, 12H, 4OAc), and
1.061 (s, 9H, (CH ₃ ) ₃ C).

[0030]

Example 7 Synthesis of Compound 13 Compound 11 (103.6 mg, 54.6 μmol) was dissolved in thioacetic acid (1 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by gel filtration (Sephadex LH-20, 90 ml, methanol) and then flash chromatography (Wako Gel C-300, 1
2 g, 19: 1 CHCl ₂ -THF) to give compound 13 (87.9
mg, 84.2%) was obtained. [Α] _D + 16.2 ° (c 0.80, CHCl ₃ ) Rf 0.36 3: 2 Toluene-AcOEt in elemental analysis C ₁₀₇ H ₁₁₈ N ₂ O ₃₀ Calculated value: C, 67.21; H,
6.22; N, 1.47 Found: C, 66.91; H, 6.23; N, 1.42 ¹ Hn. Mr Data (This compound is 13: 7 in CDCl ₃
Exists in the ratio of): δH (CDCl ₃ , 24 ℃) 7.836
(m, 2H, aromatic hydrogen), 7.741 (m, 2H, aromatic hydrogen), 6.
124 (d, 0.65H, J = 9.5 Hz, NH), 6.018 (d, 0.35H, J = 10.
3 Hz, NH), 5.664 (dt, 0.65H, J = 5.5 and 10.8 Hz, H-4
c), 5.647 (dt, 0.35H, J = 5.5 and 10.8 Hz, H-4c), 5.22
8 (m, 1H, H-8c), 3.883 (s, 1.05H, 0Me), 3.763 (s, 1.9
5H, OMe), 2.427 (dd, 0.65H, J = 5.3 and 14.1 Hz, H-3
ceq), 2.266 (dd, 0.35H, J = 5.5 and 13.6 Hz, H-3ceq),
2.152 (dd, 0.65H, J = 11.7 and 13.6 Hz, H-3cax),
2.136 (dd, 0.35H, H = 11.2 and 13.7 Hz, H-3cax), 2.
036 (1.05H), 2.019 (1.95H), 1.914 (1.05H), 1.904 (1.95
H), 1.885 (1.05H), 1.860 (1.95H), 1.834 (1.05H), 1.82
7 (1.95H), 1.805 (1.95H) and 1.786 (1.05H) (10s, 15H,
OAc), 1.194 (s, 3.15H , (CH 3) 3 C) and 1.187 (s, 5.8
5H, (CH ₃ ) ₃ C).

[0031]

Example 8 Synthesis of Compounds 14 , 15 , 16 and 17 Compound 13 (97.5 mg), 51.0 μmol) and 20% Pd (OH) ₂ -C (362
mg) in MeOH (10 ml) under hydrogen gas atmosphere and stirred at room temperature for 48 hours. The reaction solution was filtered, and the filtrate was dried under reduced pressure. The residue was dissolved in pyridine (1 ml), dimethylaminopyridine (12.4 mg, 0.1 mmol) and acetic anhydride (1 ml) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was evaporated to dryness under reduced pressure, the residue was purified by gel filtration (Sephadex LH-20, 130 ml, MeOH), and then HPLC (GL Science, Inert sil PREP-SIL,
20 x 250 mm, Toluene-THF 7: 3, 16 ml / min)
HPLC (GL Science Inert sil PREP-SIL, 20 x 2
50 mm, AcOEt, 16 ml / min) for re-purification to obtain compound 14 (11.9 mg, 15.3%), compound 15 (10.1 mg, 13.0%), compound 16 (21.0 mg, 26.9%) and Compound 17 (20.8 mg, 26.6%)
Got

14 15 [α] _D + 40.9 ° (c 0.33, CHCl ₃ ) [α] _D + 17.4 ° (c 0.56, CHCl ₃ ) Rf 0.38 3: 2 Toluene-Rf 0.42 3: 2 Toluene in THF -THF Rf 0.38 AcOEt Rf 0.42 AcOEt 16 17 (α) _D + 17.9 ° (c 0.66, CHCl ₃ ) (α) _D − 1.4 ° (c 1.23, CHCl ₃ ) Rf 0.37 3: 2 Toluene-THF Medium Rf 0.42 3: 2 Toluene-THF Medium Rf 0.33 AcOEt Medium Rf 0.37 AcOEt Medium 14 (α form) ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.819 (m, 2H, aromatic hydrogen), 7.730 (m, 2H, aromatic hydrogen), 6.305 (d, 1H, J = 3.
7 Hz, H-1a), 6.069 (d, 1H, J = 7.3 Hz, NH), 5.829 ((d
d, 1H, J = 3.3 and 11.0 Hz, H-3d), 5.575 (dd, 1H, J =
2.9 and 9.9 Hz, H-8c), 5.498 (dt, 1H, J = 5.6 and 1
1.0 Hz, H-4c), 5.480 (t, 1H, J = 9.7 Hz, H-3a), 5.367
(d, 1H, J = 3.3 Hz, H-4d), 5.244 (d, 1H, J = 2.2 and
9.5 Hz, H-7c), 5.123 (d, 1H, J = 8.4 Hz, H-1d), 5.004
(dd, 1H, J = 7.3 and 10.6 Hz, H-2b), 4.987 (dd. 1H,
J = 3.7 and 10.3 Hz, H-2a), 4.879 (dd, 1H, J = 2.9 and
11.0Hz, H-6c), 4.630 (d, 1H, J = 7.7 Hz, H-1b), 4.338
(dd, 1H, J = 2.4 and 10.1 Hz, H-3b), 4.284 (dd, 1H, J
= 2.6 and 9.2 Hz, H-9c), 4.105 (t, 1H, J = 10.6 Hz,
H-5c), 3.981 (dd, 1H, J = 4.2 and 9.0 Hz, H-9'c),
3.930 (s, 3H, OMe), 3.596 (br. D, 1H, J = 2.2 Hz, H-4
b), 3.432 (td, 1H, J = 7.7 and 11.0 Hz, H-2d), 2.955
(dd, 1H, J = 4.4 and 12.8 Hz, H-3ceq), 2.258, 2.17
1, 2.164, 2.143, 2.109, 2.098, 2.091, 2.072, 2.030,
2.008, 1.994, 1.942 and 1.834 (13s, 39H, 13OAc),
1.782 (t, J = 11.0 Hz, H-3cax), and 1.135 (s, 9H, (CH
₃ ) ₃ C). Compound 15 (β-form) ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.817 (m, 2H, aromatic hydrogen), 7.731 (m, 2H, aromatic hydrogen), 6.072 (d, 1H) , J =
7.0 Hz, NH), 5.843 (dd, 1H, J = 3.5 and 11.2Hz, H-3
d), 5.712 (d, 1H, J = 8.4 Hz, H-1a), 5.578 (ddd, 1H, J
= 2.9, 4.0 and 9.9 Hz, H-8c), 5.493 (dt, 1H, J = 4.8
And 11.7 Hz, H-4c), 5.363 (d, 1H, J = 3.3 Hz, H-4d),
5.262 (t, 1H, J = 9.5 Hz, H-3a), 5.236 (dd, 1H, J = 2.9
And 9.5 Hz, H-7c), 5.131 (d, 1H, J = 8.1 Hz, H-1
d), 5.069 (dd, 1H, J = 8.3 and 9.9Hz, H-2a), 4.987 (d
d, 1H, J = 7.7 and 9.9 Hz, H-2b), 4.876 (dd, 1H, J =
2.9 and 11.0 Hz, H-6c), 4.618 (d, 1H, J = 7.7 Hz, H-1
b), 4.329 (dd, 1H, J = 2.6 and 10.3 Hz, H-3b), 4.272
(dd, 1H, J = 2.9 and 12.8 Hz, H-9c), 4.103 (t, 1H, J
= 10.6 Hz, H-5c), 3.973 (dd, 1H, J = 4.4 and 12.8 Hz,
H-9′c), 3.916 (t, 1H, J = 9.5 Hz, H-4a), 3.924 (s,
3H, OMe), 3.755 (ddd, 1H, J = 2.2, 5.5, and 9.5 Hz,
H-5a), 3.582 (br. D, 1H, J = 2.2 Hz, H-4b), 3.399 (td,
1H, J = 8.1 and 11.0 Hz, H-2d), 2.955 (dd, 1H, J = 5.0
And 13.0 Hz, H-3ceq), 2.246, 2.168, 2.137, 2.11
2, 2.099, 2.089, 2.071, 2.063, 2.027, 1.995, 1.988
1.948, and 1.830 (13s, 39H, 13OAc), 1.721 (t, 1H,
J = 12.5 Hz, H-3cax), and 1.144 (s, 9H, (CH ₃ ) ₃ C). Compound 16 (α-form) ¹ Hn. Mr data: δH (CDCl ₃ ) 6.302 (d, 1H, J = 3.
7 Hz, H-1a), 6.025 (d, 0.4H, J = 7.3 Hz, NHtrans), 5.9
90 (d, 0.6H, J = 7.3 Hz, NHcis), 5.840 (dd, 0.4H, J = 3.
7 and 11.4 Hz, H-3dtrans), 5.783 (dd, 0.6H, J = 3.7
And 11.4 Hz, H-3dcis), 5.537 (td, 0.6H, J = 3.3 and
9.5 Hz, H-8ccis), 5.359 (br.s, 1H, H-4d), 5.156 (d
d, 0.6H, J = 2.6 and 9.9 Hz, H-7ccis), 5.124 (dd,
0.4H, J = 2.6 and 9.9 Hz, H-7ctrans), 5.091 (d, 1H,
J = 8.4 Hz, H-1d), 4.982 (dd, 1H, J = 3.7 and 10.3 H
z, H-2a), 4.798 (dd, 0.4H, J = 2.9 and 11.0 Hz, H-6
ctrans), 4.793 (dd, 0.6H, J = 2.9 and 11.0 Hz, H-6cc
is), 4.605 (d, 0.6H, J = 8.1Hz, H-1bcis), 4.594 (d, 0.
4H, J = 7.7 Hz, H-1btrans), 4.320 (dd, 0.4H, J = 2.4 and 10.4 Hz, H-3btrans), 3.892 (s, 1.8H, OMecis), 3.
881 (s, 1.2H, OMetrans), 3.515 (d, 0.4H, J = 2.2 Hz, H
-4btrans), 3.566 (d, 0.6H, J = 2.2 Hz, H-4bcis), 3.45
4 (td, 0.6H, J = 8.1 and 10.6 Hz, H-2dcis), 3.401 (t
d, 0.4H, J = 7.7 and 11.0 Hz, H-2dtrans), 2.930 (dd,
0.6H, J = 4.8 and 13.2 Hz, H-3ceg cis), 2.892 (dd,
0.4H, J = 5.1 and 12.8 Hz, H-3ceq cis), 2.818 (m,
1.2H, cyclohexane ring H-1 and H-2cis), 2.711 (q,
0.4H, J = 7.0 Hz, cyclohexane ring H-1 or H-2trans),
2.641 (q, 0.4H, J = 7.3 Hz, cyclohexane ring H-1 or H
-2trans), 2.228, 2.209, 2.162, 2.159, 2.148, 2.14
0, 2.097, 2.086, 2.060, 2.044, 2.030, 2.022, 2.01
5, 2.000, 1.990, 1.969 and 1.954 (17S, 39H, OAc),
And 1.131 (s, 9H, (CH ₃ ) ₃ C). Compound 17 (β-form) ¹ Hn. Mr Data: δH (CDCl ₃ ) 6.017 (d, 0.4H, J =
7.0 Hz, NHtrans), 5.982 (d, 0.6H, J = 7.3 Hz, NHtci
s), 5.848 (dd, 0.4H, J = 3.3 and 11.7 Hz, H-3dtran
s), 5.794 (dd, 0.6H, J = 3.3 and 11.4 Hz, H-3dcis),
5.706 (d, 1H, J = 8.4 Hz, H-1a), 5.538 (td, 0.6H, J = 2.
6 and 10.3 Hz, H-8ccis), 5.477 (td.0.4H, J = 2.6 and 9.6 Hz, H-8ctrans), 5.425 (m, 1H, H-4c), 5.355 (b
rs 1H, H-4d), 5.249 (br. t, 1H, J = 9.4 Hz, H-3a),
5.149 (dd, 0.6H, J = 2.6 and 10.3 Hz, H-7ccis), 5.
116 (dd, 0.4H, J = 2.2 and 10.6 Hz, H-7ctrans), 5.09
4 (d, 1H, J = 8.4 Hz, H-1d), 5.065 (t, 1H, J = 8.4 Hz, H-
2a), 4.957 (t, 1H, J = 8.1 Hz, H-2b), 4.791 (m, 1H, H-
6c), 4.595 (d, 0.4H, J = 7.3 Hz, H-1btrans), 4.584 (d,
0.6H, J = 7.7 Hz, H-1bcis), 4.037 (dd, 0.6H, J = 4.0 and 12.8 Hz, H-9ccis), 3.886 (s, 1.8H, OMecis), 3.876
(s, 1.2H, OMetrans), 3.739 (m, 1H, H-5a), 3.554 (br.
s, 1H, H-4b), 3.423 (td, 0.6H, J = 8.1 and 11.0 Hz,
H-2dcis), 3.372 (td, 0.4H, J = 8.1 and 10.3 Hz, H-2
dtrans), 2.928 (dd, 0.6H, J = 5.1 and 12.5 Hz, H-3ce
q cis), 2.891 (dd, 0.4H, J = 5.1 and 13.2 Hz, H-3ceq
trans), 2.814 (m, 1.2H, cyclohexane ring H-1 and
H-2cis), 2.708 (q, 0.4H, J = 7.7 Hz, cyclohexane ring
H-1 or H-2trans), 2.637 (q, 0.4H, J = 6.8 Hz, cyclohexane ring H-1 or H-2trans), 2.214, 2.197, 2.160,
2.145, 2.132, 2.101, 2.084, 2.069, 2.052, 2.044,
2.031, 2.019, 2.005, 1.984, 1.975, 1.966 and 1.95
2 (17S, 39H, OAc), and 1.140 (s, 9H, (CH ₃ ) ₃ C).

[0033]

Example 9 Synthesis of Compound 18 A mixture of Compounds 14 and 15 (16.2 mg, 10.6 μmol) was dissolved in anhydrous dimethylformamide (1 ml), and hydrazine acetic acid (2.0 mg, 21.7 μmol) was added on an oil bath at 65 ° C. In addition, the mixture was stirred at the same temperature for 30 minutes. The reaction solution was diluted with chloroform (20 ml) and washed with water (10 ml). Chloroform (10 ml
After re-extraction with (x3), the chloroform layers were combined, washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by flash chromatography (C-300, 1.8 g, CHCl ₃ -MeOH 97: 3),
Compound 18 (12.8 mg, 81.3%) was obtained. [Α] _{D + 32.8 ° (c 0.76,} CHCl 3) Rf 0.15 97: 3 CHCl 3 -MeOH in ¹ Hn mr _{data:. ΔH (CDCl 3) 7.819} (m, 2H, aromatic hydrogens), 7.735 (m , 2H, aromatic hydrogen), 6.303 (d, 0.7H, J
= 7.0 Hz, NHα), 6.173 (d, 0.3H, J = 7.3 Hz, NHβ), 5.
920 (dd, 0.7H, J = 3.3 and 11.0 Hz, H-3dα), 5.845
(dd, 0.3H, J = 3.5 and 11.0 Hz, H-3dβ), 5.577 (td, 1
H, J = 3.7 and 9.5 Hz, H-8c), 5.538 (dd, 0.7H, J = 9.2
And 9.9 Hz, H-3aα), 5.491 (ddd, 1H, J = 4.8, 10.
3 and 12.1 Hz, H-4c), 5.397 (br. D, 0.7H, J = 2.6 H
z, H-1aα), 5.370 (d, 0.7H, J = 2.9 Hz, H-4dα), 5.36
4 (d, 0.3H, J = 2.6 Hz, H-4dβ), 5.275 (t, 0.3H, J = 9.5
Hz, H-3aβ), 5.249 (dd, 0.7H, J = 2.6 and 9.9 Hz,
H-7cα), 5.241 (dd, 0.3H, J = 2.9 and 9.9 Hz, H-7c
β), 5.159 (d, 0.7H, J = 8.1 Hz, H-1dα), 5.131 (d, 0.
3H, J = 8.4 Hz, H-1dβ), 5.007 (dd, 0.7H, J = 8.1 and 1
0.3 Hz, H-2bα), 4.987 (dd, 0.3H, J = 8.1 and 10.6
Hz, H-2bβ), 4.880 (dd, 1H, J = 2.6 and 10.6 Hz, H-6
c), 4.798 (dd, 0.7H, J = 3.7 and 10.3 Hz, H-2aα), 4.
778 (dd, 0.3H, J = 8.1 and 9.9 Hz, H-2aβ), 4.692 (br.
t, 0.3H, J = 7.7 Hz, H-1aβ), 4.611 (d, 1H, J = 7.7 Hz,
H-1b), 4.332 (dd, 0.3H, J = 2.8 and 9.9 Hz, H-3b
β), 4.329 (dd, 0.7H, J = 2.6 and 10.3 Hz, H-3bα),
4.100 (t, 1H, J = 10.6 Hz, H-Sc), 3.926 (s, 0.9H, OMe
β), 3.923 (s, 2.1H, OMeα), 3.852 (t, 0.7H, J = 9.2
Hz, H-3aα), 3.829 (t, 0.3H, J = 9.5 Hz, H-3aβ), 3.5
84 (d, 0.3H, J = 2.2 Hz, H-4bβ), 3.580 (d, 0.7H, J = 2.
2 Hz, H-4bα), 3.399 (td, 0.3H, J = 8.1 and 11.0 H
z, H-2dβ), 3.338 (td, 0.7H, J = 8.1 and 10.6 Hz, H
-2dα), 2.975 (dd, 1H, J = 5.1 and 12.6 Hz, H-3ce
q), 2.246, 2.171, 2.138, 2.134, 2.109, 2.104, 2.10
1, 2.098, 2.071, 2.067, 2.028, 1.995, 1.991, 1.832
And 1.828 (16s, 36H, OAc), 1.725 (t, 1H, J = 12.5 H
z, H-3cax), and 1.190 (s, 9H, (CH ₃ ) ₃ C).

[0034]

Example 10 Synthesis of Compound 19 A mixture of Compounds 16 and 17 (32.8 mg) was converted into Compound 19 (22.3 mg, 69.9%) by the same method as in the synthesis of Compound 18 . [Α] _D + 14.4 ° (c 0.88, CHCl ₃ ) Rf 0.39, 0.36 19: 1 CHCl _{3 in} MeOH ¹ Hn. Mr Data: δH 6.237 (d, 0.28H, J = 7.0 H
z, NHαtrans), 6.209 (d, 0.42H, J = 7.0 Hz, NHαci
s), 6.113 (d, 0.12H, J = 7.3 Hz, NHβtrans), 6.007 (d,
0.18H, J = 7.0 Hz, NHβcis), 5.914 (dd, 0.28H, J = 3.7
And 11.4 Hz, H-3dαtrans), 5.868 (dd, 0.42H, J =
3.3 and 11.0 Hz, H-3dαcis), 5.846 (dd, 0.12H, J =
3.7 and 11.0 Hz, H-3dβtrans), 5.792 (dd, 0.18H,
J = 3.7 and 11.4 Hz, H-3dβcis), 5.392 (d, 0.7H, J =
3.7 Hz, H−1aα), 5.360 (br.s, 1H, H-4d), 5.155 (m,
1H, H-7c), 4.975 (m, 1H, H-2b), 4.795 (dd, 0.7H, J =
3.7 and 10.3 Hz, H-2aα), 4.585 (d, 0.4H, J = 7.7
Hz, H-1btrans), 4.575 (d, 0.6H, J = 7.7 Hz, H-1bci
s), 3.886 and 3.876 (2s, 3H, OMe), 3.554 (m, 1H, H-4
b), 3.375 (m, 1H, H-2d), 2.931 (m, 1H, H-3ceq), 2.816
(m, 1.2H, cyclohexane ring H-1 and H-2cis), 2.709
(q, 0.4H, J = 7.3 Hz, cyclohexane ring H-1 or H-2tra
ns), 2.788 (q, 0.4H, J = 6.6 Hz, cyclohexane ring H-1
or H-2 trans), 2.214, 2.196, 2.163, 2.148, 2.131,
2.096, 2.092, 2.083, 2.058, 2.055, 2.030, 2.020,
2.014, 1.999, 1.986, 1.971, 1.966 and 1.952 (18
s, 36H, OAc), 1.646 (m, 1H, H-3cax), and 1.187 (s,
9H, (CH ₃ ) ₃ C).

[0035]

Example 11 Synthesis of Compound 20 Compound 18 (12.7 mg, 7.7 μmol) was treated with dichloroethane (0.2
ml) and dissolve in trichloroacetonitrile (10 μl, 9
7.7 μmol) and DBU (1.8 μl, 11.6 μmol) were added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. The reaction solution was directly purified by flash chromatography (C-300, 1.0 g, 3: 2 toluene-THF) to obtain Compound 20 (13.8 mg, 99.3%). [Α] _D ＋ 40.2 ° (c 0.92, CHCl ₃ ) Rf 0.50 11: 9 Toluene-THF in ¹ Hn. Mr Data: δH (CDCl ₃ ) 8.650 (s, 1H, C = N
H), 7.818 (m, 2H, aromatic hydrogen), 7.735 (m, 2H, aromatic hydrogen), 6.522 (d, 1H, J = 3.7 Hz, H-1a), 6.020 (d, 1H, J
= 7.3 Hz, NH), 5.842 (dd, 1H, J = 3.3 and 11.0 Hz, H
-3d), 5.573 (m, 2H, H-8c and H-3a), 5.495 (ddd, 1
H, J = 4.8, 10.3 and 12.1 Hz, H-4c), 5.366 (d, 1H,
J = 3.3 Hz, H-4d), 5.241 (dd, 1H, J = 2.9 and 9.9 Hz,
H-7c), 5.133 (d, 1H, J = 8.1 Hz, H-1d), 5.076 (dd, 1
H, J = 3.7 and 10.3 Hz, H-2a), 5.016 (dd, 1H, J = 7.7
And 9.9 Hz, H-2b), 4.875 (dd, 1H, J = 2.9 and 1
1.0 Hz, H-6c), 4.659 (d, 1H, J = 7.7 Hz, H-1b), 4.336
(dd, 1H, J = 2.6 and 10.3 Hz, H-3b), 4.267 (dd, 1H,
J = 5.5 and 11.4 Hz, H-9c), 4.102 (t, 1H, J = 10.3 H
z, H-5c), 3.591 (br. d, 1H, J = 1.8 Hz, H-4b), 3.415 (t
d. 1H, J = 7.7 and 10.6Hz, H-2d), 2.961 (dd, 1H, J =
4.8 and 12.8 Hz, H-3ceq), 2.260, 2.173, 2.142,
2.110, 2.093, 2.073, 2.071, 2.029, 2.014, 1.992,
1.943 and 1.831 (12s, 36H, 12OAc), 1.729 (t, 1H, J
= 12.8 Hz, H-3cax), and 1.141 (s, 9H, (CH ₃ ) ₃ C).

[0036]

Example 12 Synthesis of compound 21 Compound 19 (22.3 mg) was converted to compound 21 (23.0 mg, 94.0%) by the same method as for the synthesis of compound 20 . [Α] _D + 26.3 ° (c 0.76, CHCl ₃ ) Rf 0.35 13: 7 Toluene-THF in ¹ Hn. Mr Data: δH (CDCl ₃ ) 8.646 (s, 1H, C = N
H), 6.518 (d, 1H, J = 3.7Hz, H-1a), 5.981 (d, 0.4H, J =
7.3 Hz, NHtrans), 5.984 (d, 0.6H, J = 7.3 Hz, NHcis),
5.856 (dd, 0.4H, J = 3.3 and 11.4 Hz, H-3dtrans),
5.797 (dd, 0.6H, J = 3.3 and 11.0 Hz, H-3dcis), 5.568
(m, 1.6H, H-3a and H-8ccis), 5.479 (td, 0.4H, J = 3.
3 and 9.5 Hz, H-8ctrans), 5.359 (br.s, 1H, H-4
d), 5.153 (dd, 0.6H, J = 2.9 and 9.9 Hz, H-7ccis),
5.121 (dd, 0.4H, J = 2.2 and 9.6 Hz, H-7ctrans), 5.
098 (d, 1H, J = 8.4 Hz, H-1d), 5.072 (dd, 1H, J = 3.7
And 10.3 Hz, H-2a), 4.989 (dd, 0.4H, J = 7.3 and
9.5 Hz, H-2btrans), 4.984 (dd, 0.6H, J = 7.7 and 10.
3 Hz, H-2bcis), 4.793 (dd, 0.4H, J = 3.7 and 10.6 H
z, H-6ctrans), 4.786 (dd, 0.6H, J = 2.9 and 10.6 Hz,
H-6ccis), 4.633 (d, 0.4H, J = 7.7 Hz, H-1btrans), 4.
623 (d, 0.6H, J = 7.7 Hz, H-1bcis), 4.317 (dd, 0.4H, J
= 2.6 and 9.9 Hz, H-3btrans), 4.275 (dd, 0.6H, J = 2.
6 and 10.3 Hz, H-3bcis), 3.890 (s, 1.8H, OMecis),
3.880 (s, 1.2H, OMetrans), 3.563 (br.s, 1H, H-4b),
3.435 (td, 0.6H, J = 8.1 and 11.0 Hz, H-2dcis), 3.
379 (td, 0.4H, J = 7.3 and 11.0 Hz, H-2dtrans), 2.93
6 (dd, 0.6H, J = 4.8 and 12.8 Hz, H-3ceqcis), 2.900 (d
d, 0.4H, J = 5.1 and 13.2 Hz, H-3ceqtrans), 2.815
(m, 1.2H, cyclohexane ring H-1 and H-2cis), 2.709
(q, 0.4H, J = 7.7 Hz, cyclohexane ring H-1 or H-2tran
s), 2.638 (q, 0.4H, J = 6.6 Hz, cyclohexane ring H-1o
r H-2 trans), 2.356, 2.230, 2.211, 2.166, 2.151,
2.138, 2.099, 2.077, 2.066, 2.062, 2.022, 2.015, 2.
000, 1.994, 1.989, 1.967, and 1.953 (17s, 36H, OA
c), and 1.139 (s, 9H, (CH ₃ ) ₃ C).

[0037]

Example 13 Synthesis of Compound 23 Compound 20 (13.8 mg, 8.5 μmol), 22 (12.9 mg, 17.1 μmo)
l) and molecular sieves 4A (51 mg) of CHCl ₃ (0.7
BF ₃ OEt ₂ (2.1 μl, 17.1 μmo) at −18 °
l) was added, and the mixture was stirred at the same temperature for 1 hour. After stirring at 0 ° for 2 hours, the reaction solution was diluted with CHCl ₃ (20 ml) and filtered through Celite. The filtrate was washed with saturated aqueous sodium hydrogen carbonate (20 ml), and the washings were re-extracted with chloroform (20 ml x 2). The chloroform layers were combined, washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (C-300, 3g, 39: 1 CHCl ₃ -MeOH) to obtain compound 23 (6.4 mg, 34.0%). [Α] _D + 17.8 ° (c 0.39, CHCl ₃ ) Rf 0.34 13: 7 Toluene-THF in ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.993 (dd, 2H, J =
1.5 and 7.0 Hz, C ₆ H ₅ CO), 7.819 (m, 2H, aromatic hydrogen), 7.735 (m, 2H, aromatic hydrogen), 1.541 (tt, 1H, J = 1.5
And 7.3 Hz, C ₆ H ₅ CO), 7.422 (t, 2H, J = 7.7 Hz, C ₆ H
₅ CO), 6.236 (d, 1H, J = 7.3 Hz, NH-2d), 5.869 (td, 1H,
J = 6.6 and 14.7 Hz, H-5cer), 5.847 (dd, 1H, J = 3.3
And 11.4 Hz, H-3d), 5.756 (d, 1H, J = 9.5 Hz, NHce
r), 5.569 (td, 1H, J = 3.3 and 9.5 Hz H-8c), 5.544
(t, 1H, J = 7.3 Hz, H-3cer), 5.460 (dd, 1H, J = 7.7 and 15.4 Hz, H-4cer), 5.360 (d, 1H, J = 2.9 Hz, H-4d),
5.234 (dd, 1H, J = 2.6 and 9.9 Hz, H-7c), 5.185 (t,
1H, J = 9.5 Hz, H-3a), 5.125 (d, 1H, J = 8.4 Hz, H-1d),
4.963 (dd, 1H, J = 7.7 and 10.3 Hz, H-2b), 4.926 (d
d, 1H, J = 7.7 and 9.9 Hz, H-2a), 4.878 (dd, 1H, J =
2.6 and 10.6 Hz, H-6c), 4.574 (d, 1H, J = 7.7 Hz, H-1
b), 4.456 (m, 1H, H-2cer), 4.419 (d, 1H, J = 7.7Hz, H-
1a), 4.321 (dd, 1H, J = 2.6 and 9.9 Hz, H-3b), 4.09
5 (t, 1H, J = 10.5Hz, H-5c), 3.923 (s, 3H, OMe), 3.829
(t, 1H, J = 9.5 Hz, H-3a), 3.600 (dd, 1H, J = 4.0 and
9.9 Hz, H-1cer), 3.577 (d, 1H, J = 2.2 Hz, H-4b), 3.5
27 (m, 1H, H-5a), 3.377 (td, 1H, J = 7.7 and 11.0 Hz,
H-2d), 2.947 (dd, 1H, J = 4.8 and 12.8 Hz, H-3ceq),
2.210, 2.173, 2.132, 2.124, 2.091, 2.057, 2.027,
1.984, 1.976, 1.947, 1.893 and 1.828 (12s, 36H, 1
2OAc), 1.714 (t, 1H, 12.7Hz, H-3cax), 1.151 (S, 9H,
(CH ₃ ) ₃ C), 0.880 (t, 3H, J = 7.3 Hz, (CH ₂ CH ₃ ), and 0.
876 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ) .

[0038]

Example 14 Synthesis of Compound 24 Compound 21 (21.8 mg) and 22 (20.1 mg) were condensed in the same manner as in the synthesis method of Compound 23 to obtain Compound 24 (9.4 mg, 32.3%). (Α) _D + 3.9 ° (c 0.52, CHCl ₃ ) Rf 0.40 13: 7 Toluene-THF in ¹ Hn. Mr Data: δH (CDCl ₃ ) 7.991 (d, 2H, J = 7.
3 Hz, C ₆ H ₅ CO), 7.542 (t, 1H, J = 7.7 Hz, C ₆ H ₅ CO), 7.4
24 (t, 2H, J = 7.7 Hz, C ₆ H ₅ CO), 6.183 (d, 0.4H, J = 7.7 H
z, NH-2dtrans), 6.144 (d, 0.6H, J = 7.3 Hz, NH-2dci
s), 5.867 (td 1H, J = 6.6 and 15.0 Hz, H-5cer), 5.797
(dd, 0.6H, J = 3.3 and 11.0 Hz, H-3dcis), 5.750 (d,
1H, J = 9.2 Hz, NHcer), 5.542 (t, 1H, J = 7.5 Hz, H-3c
er), 5.459 (dd, 1H, J = 7.3 and 15.0 Hz, H-4cer),
5.429 (m, 1H, H-4c), 5.353 (br. D, 1H, J = 2.6 Hz, H-4
d), 5.173 (t, 1H, J = 9.2 Hz, H-3a), 5.089 (d, 1H, J =
8.1 Hz, H-1d), 4.928 (m, 2H, H-2a and H-2b), 4.79
9 (dd, 0.4H, J = 2.6 and 11.0Hz, H-6ctrans), 4.790 (d
d, 0.6H, J = 2.9 and 10.6 Hz, H-6ccis), 4.554 (d, 0.
4H, J = 7.0 Hz, H-1btrans), 4.542 (d, 0.6H, J = 8.1 Hz,
H-1bcis), 4.454 (m, 1H, H-2cer), 4.413 (d, 1H, J = 8.1
Hz, H-1a), 4.301 (br. D, 1H, J = 10.3 Hz, H-3b), 3.8
84 (s, 1.8H, 0Mecis), 3.875 (s, 1.2H, OMetrans), 3.8
18 (t, 1H, J = 9.7 Hz, H-4a), 3.596 (dd, 1H, J = 3.9 and 10.1 Hz, H-1cer), 3.551 (br.s, 1H, H-4b), 3.507
(m, 1H, H-5a), 3.379 (m, 1H, H-2d), 2.920 (dd, 0.6H,
J = 4.4 and 12.8 Hz, H-3ceqcis), 2.881 (dd, 0.4H, J =
5.1 and 12.8 Hz, H-3ceqtrans), 2.815 (m, 1.2H, cyclohexane ring H-1 and H-2cis), 2.709 (q, 0.4H, J =
7.7 Hz, cyclohexane ring H-1 or H-2trans), 2637 (q,
0.4H, J = 6.6 Hz, cyclohexane ring H-1 or H-2tran
s), 2.175, 2.164, 2.160, 2.156, 2.151, 2.128, 2.11
2, 2.074, 2.048, 2.046, 2.020, 2.006, 1.980, 1.96
2, 1.956, 1.954, 1.948, 1.889, and 1.885 (19s, 36
H, OAc), 1.147 (s , 9H, (CH 3) 3 C), 0.879 (t, 3H, J = 6.5
Hz, CH ₂ CH ₃ ) , and 0.878 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ) .

[0039]

Example 15 Synthesis of Compound 25 Lithium iodide (3.5 mg, 26.2 μmol) was vacuum dried on a 90 ° oil bath for 21 hours, and Compound 23 (4.0 mg, 1.8 mg) was added thereto.
A solution of μmol) in anhydrous pyridine (0.20 ml) was added, and the mixture was stirred at 110 ° for 2 hours. Gel filtration of the reaction mixture (Sephadex L
After purification with H-20, 5 ml, MeOH), re-purification with flash chromatography (Wako Gel FC-40, 0.6 g, 9: 1 CHCl ₃ -MeOH) gave compound 25 (3.2 mg, 80.3%). . [Α] _D + 19.0 ° (c 0.21, CHCl ₃ ) Rf 0.53 17: 3 CHCl ₃ -MeOH in Hn ¹ mr. Data: δH (CD ₃ OD) 7.999 (d, 2H, J = 7.
3 Hz, C ₆ H ₅ CO), 7.862 (m, 2H, aromatic hydrogen), 7.806 (m,
2H, aromatic hydrogen), 7.591 (t, 1H, J = 7.3 Hz, C ₆ H ₅ CO),
7.460 (t, 2H, J = 7.7 Hz, C ₆ H ₅ CO), 5.872 (td, 1H, J = 7.
3 and 15.0 Hz, H-5ccer), 5.726 (dt, 1H, J = 5.1 and 11.0 Hz, H-4c), 5.561 (t, 1H, J = 6.8Hz, H-3cer),
5.507 (dd, 1H, J = 7.7 and 15.0 Hz, H-4cer), 5.311
(d, 1H, J = 2.9 Hz, H-4d), 2.872 (dd, 1H, J = 5.1 and
11.0 Hz, H-3ceq), 2.152, 2.146,2.143, 2.110, 2.06
2, 2.038, 1.998, 1.987, 1.974, 1.912 (6H) and 1.77
8 (11S, 36H, 120Ac), 1.580 (t, 1H, J = 11.0, Hz, H-3ca
x), 1.152 (S, 9H, (CH ₃ ) ₃ C), 0.896 (t, 3H, J = 7.3 Hz,
CH ₂ CH ₃ ), and 0.894 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

[0040]

Example 16 Synthesis of compound 26 Compound 24 (5.9 mg) was converted into compound 26 (5.8 mg, 98.6%) by the same method as for the synthesis of compound 25 . [Α] _{D + 12.9 ° (c 0.39,} CHCl 3) Rf 0.48 17: 3 CHCl 3 -MeOH in ¹ Hn mr _{data:. ΔH (CO 3 OD)} 7.997 (d, 2H, J = 8.
0 Hz, C ₆ H ₅ CO), 7.592 (t, 1H, J = 7.3 Hz, C ₆ H ₅ CO), 7.4
60 (d, 2H, J = 7.7 Hz, C ₆ H ₅ CO), 5.880 (td, 1H, J = 6.2
And 15.4 Hz, H-5cer), 5.664 (m, 1H, H-4c), 5.560
(t, 1H, J = 7.7 Hz, H-3cer), 5.497 (dd, 1H, J = 6.6 and 15.4 Hz, H-4cer), 5.434 (m, 0.6H, H-8ccis), 5.34
8 (m, 0.4H, H-8ctrans), 5.305 (d, 1H, J = 2.6 Hz, H-4
d), 4.635 (d, 2H, J = 8.1 Hz, H-1a and H-1b), 2.166,
2.140, 2.129, 2.101, 2.073, 2.032, 2.029, 2.019,
2.001, 1.996, 1.965, 1.961, 1.934 and 1.914 (14s,
36H, 0Ac), 1.149 (s , 9H, (CH 3) 3 C), 0.897 (t, 3H, J = 6.
4 Hz, CH ₂ CH ₃ ), and 0.895 (t, 3H, J = 6.4 Hz, CH ₂ C
H ₃ ).

[0041]

Example 17 Synthesis of Compound 27 Method A: Compound 25 (1.7 mg, 0.8 μmol) was dissolved in 40% methylamine-MeOH solution (0.4 ml) and stirred at room temperature for 50 hours. The reaction mixture was evaporated to dryness under reduced pressure, 1N-NaOH (16 μl) was added to the residue, and gel filtration (Sephadex LH-20, 10 ml, 5: 4: 1 CH) was used.
Cl ₃ —MeOH—H ₂ O) was purified to obtain Compound 27 (0.7 mg, 63.1%).

Method B: Compound 26 (2.8 mg, 1.3 μmol) was added with Et.
Dissolve in OH (0.2 ml), add MeNHNH ₂ (0.4 ml), and add 4 at 75 °.
It was stirred for 8 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was HPTLC.
(Merck Silica Gel 60 F _254, 5: 4: 1 CHCl ₃ -MeOH-
H ₂ O), 1N-NaOH (13 μ1) was added, and gel filtration (Sephadex LH-20, 10 ml, 5: 4: 1 CHCl ₃ -MeOH-H ₂ O) was used to purify compound 27 (0.8 mg). , 43.8%). [Α] _D -8.8 ° (c 0.05, pyridine) Rf 0.29 5: 4: 1 CHCl 3 -MeOH-H 2 O in mass spectrum: m / z 1425 (MH) - 1 Hn mr data:. ΔH (r: r CDCl ₃ -CD ₃ OD), 5.692
(td, 1H, J = 6.6 and 15.4 Hz, H-5cer), 5.455 (dd, 1
H, J = 7.3 and 15.4 Hz, H-4cer), 4.844 (d, 1H, J = 8.4
Hz, H-1d), 4.407 (d, 1H, J = 8.1 Hz, H-1b), 4.291 (d,
1H, J = 7.7 Hz, H-1a), 4.095 (t, 1H, J = 7.7 Hz, H-3ce
r), 2.778 (t, 1H, J = 9.7 Hz, H-5c), 2.681 (dd, 1H, J =
4.8 and 12.5 Hz, H-3ceq), 2.176 (t, 2H, J = 7.7 Hz,
NHCO CH ₂ ), 2.037 (s, 3H, NH Ac ), 1.829 (t, 1H, J = 12.1
Hz, H-3cax), and 0.891 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).
_.

Front Page Continuation (72) Inventor Kenkichi Tomita 2-11-1, Nishishinjuku, Shinjuku-ku, Tokyo Mect Co., Ltd. (72) Inventor Tomoya Ogawa 3-6-6-3-101 Kichijoji Kitamachi, Musashino City, Tokyo

Claims (4)

[Claims] 1. De-N-acetyl G represented by the following formula (I):
M ₂ and its salts. [Chemical 1] _{2. An} intermediate for producing de-N-acetyl GM _{2 according to} claim 1, which is represented by the following general formula (II): (In the formula, R ¹ represents an amino group or a protected amino group, R ² represents a hydrogen atom or a lower alkyl group, X represents a hydroxyl group, a hydroxyl group having a protective group, a halogen atom, -OCNHCCl
₃ or the following formula: (In the formula, R ³ represents a hydrogen atom or a hydroxyl-protecting group), and Piv represents a pivaloyl group). 3. An intermediate for the production of de-N-acetyl GM _{2 according to} claim 1, which is represented by the following general formula (III): (In the formula, R ⁴ represents an amino group or a protected amino group, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ independently represents a hydroxyl protecting group, and R ⁷ represents an amino group or a protected group. Represents an amino group or an azido group, and Piv represents a pivaloyl group). 4. An intermediate for producing de-N-acetyl GM _{2 according to} claim 1, which is represented by the following general formula (IV): (In the formula, R ⁸ represents an amino group or a protected amino group, R ⁹ represents a hydrogen atom or a lower alkyl group, R ¹⁰ represents a hydrogen atom or a hydroxyl-protecting group, and R ¹¹ independently represents a hydroxyl group. Represents a protecting group, Piv represents a pivaloyl group).