JPH03237101A - Intermediate for synthesis of glycosylphosphatidylinositol anchor and intermediate for synthesis of glycosylphosphatidylinositol anchor-related compounds - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I (R is H, benzyl, methoxybenzyl or acetyl). USE:An intermediate for synthesis of glycosylphosphatidylinositol anchor (GPI anchor) useful as a bioactive substance and capable of production of GPI anchor in a high yield. Capable of providing a useful mean for biosynthesis of GPI anchor and for dissolution of the biological role thereof. PREPARATION:Compounds of formulae III and IV (TBDPS is tert- butyldiphenylsilyl; Bn is benzyl) respectively obtained from a known compound of formula II (TBS is tert-butyldimethylsilyl) are initially reacted and protecting groups are subsequently eliminated from the resultant product. From the obtained compound, the objective compound where R is H is then synthesized through compounds of formulae V, VI and VII (R<5> is H or Ac; R is H). ln addition, compounds of formulae III-VII are new compounds.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides glycosylphosphatidylinositol (G
PI) Anchor synthesis intermediates and GPI anchor analogue synthesis intermediates.

(Prior Art) The GPI anchor represented by the formula (1) is known as a membrane binding part of a group of membrane junction proteins such as the surface antigen of the parasite Triphanosyma and animal phosphatase (Ann.
, Rev, Bioche++, Vol. 57, p. 285 (1988), Science, Vol. 239, p. 753 (1
988) Science, vol. 233, p. 967 (1986)
), the possibility of protein membrane immobilization and as a second messenger has been suggested. Also, inositol glycans containing glycosamine and choinositol (
IC) has been reported to have insulin-like activity (Science, 239.268 (1988)
, Biochem, J, 244, H1987))
.

However, examples of extraction of protein-bound C, PI anchors have been known so far (Reference: J, Ce1l.

Bioche+*, 24.79 (1984)), but the GPI anchor itself had not been isolated, and no chemical synthesis method was known.

(Problem to be Solved by the Invention) Therefore, the present invention aims to provide a synthetic intermediate useful for the base of a GPI anchor, and to provide an inositol glycan (IG) containing glucosamine and myo-inositol. do.

(Means for Solving the Problems) In order to solve the above-mentioned object, the inventors of the present invention have developed a GPI anchor. The present invention was completed by completing the chemical synthesis of the chain and selecting useful manufacturing intermediates.

That is, the present invention provides a GPI anchor intermediary intermediate represented by the following formula (II).

Il OP 0CNzC) IJHzO (wherein R independently represents hydrogen, a benzyl group, a methoxybenzyl group, or an acetyl group).

Furthermore, the present invention provides useful intermediates represented by formulas (III) to (V) for the synthesis of compounds represented by marii(n).

(In the formula, R1 independently represents a benzyl group, a methoxybenzyl group, or an acetyl group), (In the formula, Rs represents a hydrogen or acetyl group, and R2 independently represents a benzyl group or a methoxybenzyl group)
The present invention provides synthetic intermediates for GPI anchor analogs represented by the following formulas (Vl) to (XII').

3 (wherein R2 and R3 independently represent a hensyl group or a methoxyhensyl group, and R4 represents a tert-butyldiphenyl group or an allyl group), and I! of a GPI anchor using the compound of the present invention below. Chain synthesis method and G
An example of a method for synthesizing a synthetic intermediate of a PM anchor analog is shown in a scheme.

In this scheme, Ac represents an acetyl group, MBn represents a methoxybenzyl group, Bn represents a benzyl group, pH represents a phenyl group, TBS represents a tert-butyldimethylsilyl group, and TBS represents a tert-butyldimethylsilyl group.
BDPS has a tert-butyldiphenylsilyl group, M
P represents a methoxyphenyl group.

In the scheme, compound 1 is described in Carbohydrate Research Vol. 130, p. 322 (1984), and compound 1) is described in Konstanzel Disceltation (Konst
15 (1986), 19 compounds are tetrahedron 37
Vol. 2787 (1981), and 21 compounds were published in Carbohydrate Research Vol. 93, p. 67 (1981).
, 24 compounds are carbohydrate chemistry 2
Vol.
The compounds are described in Carbohydrate Research 64S, page C3 (1978).

In the above scheme, one example of commonly used reaction reagent (A), reaction solvent (B), reaction time (C), and reaction temperature (D) is shown, but with changes obvious to those skilled in the art to these conditions. Good too.

-2 A) Allyl bromide, allyl iodide -3 C) 5hr"l night 3→4 A) 0.1M hydrochloric acid/methanol, 80% acetic acid C)
30 minutes to 1 hour - 5 C) 2 hours to overnight - 6 B) CHxCN/HzO, 'r toluene/CHffC
N/H20C) 1.5 hr to 3 hr -8 A) MeONa , KO) I , Na0HB
) THF/MeOH, THF/EtOHC)
1 hr to 3 hr -9 C) 5 hr to overnight -10 C), 1.5 hr = overnight D) Room temperature to 80°C 1-12 A) P-TsOf(, ZnC1x, BF30E
ttB) CH3CN SDMF-acetone, DMF
C) 5 hours to 1 night 0) room? ! jL~80℃ 2-13 B) THF, CH, Cj22 C)? , 5 hr~overnight D) 60~80°C 13→14a A) MeJBHz+AlIC1:l, NaBH3
CN+HCj? C) 5 hours to overnight 5-16 C) 4 hours to overnight 17→18 A) NaOMe -K2CO:l, KOH
, Na0HB) THF/Me01(, TFIF/E
tOf(C) 5hr~overnight 19→20 A) 5nC14, BFJEtz, TMSORf
B) C1(CHz)zCj! , CHtCl2
, TIIFC) 3hr~1 night D) O℃~30℃ 22→23 A) DAST, AgF B) CI (CHz)zcj! , CHzCj!
z, THF, CH3CNC) 30IIIin~
Overnight D) 01-30°C 4-25 A) TMSOTf, SnC1-, BF30Et
zB) CI! (C)Iz)zcl, ChzCf
z, THFC) 3hr~1 night D) O℃~30℃ 25→26 A) NaOMe, KzCO3, KOH, Na
0) IB) MeO) I, EtOH C) Ihr=overnight D) 0°C to 50°C 1B+20→29 A) AgOτf, AgCl04B) CHJ
Oz, CHzClt- CI CHzCH2C1, Et! 0 0-31 A) DAST, AgF B) CI CCHtrCl, CHzClz
, T)IP, CH3CNC) 30
min~1 nightD) 0℃~30℃ 31 + 10→32 ^) CpzZrClz, Cpz)IfCj! z
B) EtzO, CHzCj! t, CICC
Hz) tc12-33 A) NaOMe SK, CO3, KOH, Na0
HB) THF/MeOH, THF/EtO) IC)
5hr~1 night 2-34 A) AcCl, Acz0 35+28→36 A) CuBr/nBuJBr, HgBrz/CuB
rz/nBuaNBrB) C1(CHz)zCj'
, CLCj! z, Etz06-37 A) CAN, DDQ B) CHsCN/HzO, To/L/F/CH3C
N/H207-38 A) DAST, AgF B) C1 (CHz)zCj? , CLCjl'
t, THF, C)l:IcNC) 30wi
n~1 night D) 0°C to 30°C 34+38-39 A) CpzZrCI Z , cpt) Irc l
2B) Et, 0, CHzC/2, CI! (
CHz”)zcIC) 4hr~overnight 9-40 A) NaOMe, KzCOx, KO)I
, Mail(B) T)IF/MeO)IST
HF/EtOHC) 5hr~overnight 40+41-42 2-43 A) NaOMe 5KzCO3, KO) IX
Na0) IB) THF/MeOH, THF/EtO
HC) 5hr=1 night 43+23-44 A) CpzZrClz, CpJf(JzB)
Et, 0, CLClz, C1(CHz)zCj'
44→45 B) THF/MeOH, THF/EtO) 1°B)
MeOH-MeOH/HzO C) 2hr~1 night T) IF/DMF 33→■ 010χPd/C, 20XPd/(OR)2/CB)
MeO)I/THF, EtOH/TFIFC)
5 hours ~ 29 → 50 per day A) NaOMe, NaOH,, KO) IB)
MeO) 1/THF, EtOH/THFC) 3 hours to 1 day A) BnBr,, Bnl BuJF
DASTB) THF, CHzCj! z
THF (C1CHzlz, THFC) 6 hours to 1 day 3 to 1 day 0.5 hours to 2 hours53 +
10→54 A) CpzZrCl z, CpJfCj! zB
) Et, 01 (CI CHz) 2, C) ltcj
l! zC) 5 hours to 1 day 54 → 55 + 56 A) CAN, DDQ B) C) licN/)lzO, φMe/CHtCN
/HzO, CH2Cf! z/HzOC) 1 hour~
3 hours 56→X A) 20$Pd/(OH)! /C,10! Pd/C
B) MeOH/THF C) 3 hours to 1 day 46→■ A) NaOMe, NaOH, KOHB) T
HF/MeOH, THF/EtOHC) 2 hours to 1
Day 40 (α)→■ A) 20XPd/(OH)! /C, 10XPd/C
B) THP/MeOH, THF/EtOHC)
2 hours to 1 day 43→■ A) NaOMe S NaOH, KOHB) T
HF/MeOH, TIP/EtOHC) 3 hours to 1
Day A) AgC10a B) (CjICHz)z , CH, CIR1Et
! OC) 2 hours to 5 hours 48→XI A) NaOMe ,, Na0)! , KO)IB)
T) IF/MeOH, THF/EtOHC) 5
Time ~ 1 day 49→x■ A) NaOMe,, NaOH, KOHB) T
HF/MeOH,T)IF/EtOHC) 4 hours~
1 day (effects of the invention) By using the compound of the present invention, a GPI anchor useful as a physiologically active substance can be produced in high yield. In addition, by using a synthetic intermediate of the GPI anchor interlinkage intermediate GP IQ limb, it provides a useful means for elucidating the biosynthesis and physiological role of the GPI anchor.

The present invention will be explained in more detail by examples below.
The invention is not limited to the examples. The compound number in the examples is the compound number in the above scheme.

1→2 1.2:5.6-di-O-cyclohexylidenemyo-inositol 1 67.6 g (198,8 mmoi) and di-n-butyltin oxide 49.5 g (198,8
The resulting solution was dissolved in toluene (1), and the produced water was distilled off using a Dean-Stark apparatus under heating and reflux. After 3 hours, the solvent was distilled off and the residue contained 41.97 cesium fluoride.
g (276.3 mmol) was added thereto, and the mixture was dried for 1.5 hours using a vacuum pump. Next, dimethylformide (hereinafter abbreviated as DMF) 1) and allyl bromide 21.7m (2
After stirring at room temperature overnight, the solvent was distilled off under reduced pressure.

Ethyl acetate (AcOEt) was added to the residue, and water and saturated (sa)
t,) After washing with an aqueous NaCl solution, it was dried over anhydrous MgSO4, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (5/95 acetone/toluene) to obtain 259.91 g (79.3%).

Rf O,5 (5/95 acetone/toluene)'HNM
R(CDCl x>δ; 1.39-1.81(m,
20H), 2.59 (d.

1B, J, 1.53. OH), 3.49(dd,
LH, J, 7.93.10.68°H-5), 3.
83(1)1. dd, J.2.13.7.93.
I(-4), 3.99(dt, IH, J・3
．． 66, 1.83. H-3), 4.14 (dat
, J.12.67, 5.65. 1.53), 4
．． 17 (dd, J・7.93. 10.68°H-
6), 4.24 (ddt, 18. Jyo12.8
2. 5.50. 1.53), 4.34(t, I
I, J.7.48. H-1), 4.43 (dd
, IH, J・3.66°6.33. H-2),
5.20 (dq, IH, J・10.68. 1.5
2) , 5.33 (dq, 18. J=17.
40. 1.52) , 5.94(m, I[()
Elemental analysis (Anal) Calculated value (Calcd for)
CzIHz+01!4CHCj? 3:C, 62, 19
; H7,92 Found: C,62,13, H,8,05 2→3 Compound 2 22.8 g (60 mraall")
Dissolved in MF350-, 6g of 60% sodium hydride (
150 Ilmol) was added and stirred at room temperature for 30 minutes, followed by 9.8d of methoxybenzyl chloride (72ramol).
) was added thereto, and the mixture was stirred at room temperature. After 6.5 hours, the reaction solution was poured into ice water and extracted with chloroform.
After washing with an aqueous NaCl solution, it was dried over anhydrous Mg5Oa, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (2,5/97.5 ethyl acetate/toluene),
3 24.65 g (80.8%) was obtained.

Rf O, 43 (5/95 ethyl acetate/toluene)
') INMR (CDCL) δ; 1.38-1.76 (
m, 208), 3.41 (dd, LH, J・7.
63.10.68. H-5), 3.68 (t, 1)
1. J・3.35. H-3), 3.76 (dd,
IH, J. 3.05.7.62. H-4), 3.80
(s, 3B, OMe), 3.97-4.02 (m,
It(), 4.08(dd.

IH, Jyo7.4B, 10.53. H-6), 4
．． 07-4.12 (m, 18), 4.27 (t, L
H, J=7.17. I(-1), 4.32(dd,
l) l, J・3.81°6.87. I(-2), 4
．． 61(d, IL J=1). 90. CHzAr)
, 4.66 (d, IH, J=1). 90. CHtA
r), 5.14-5.17 (a+.

1) 1), 5.24-5.29 (a, IH), 5.
83-5.91 (m, 1)l), 6.86 (d,
IH, J=1.83. Ar), 6.87(d, I
H, J=2-13°Ar), 7.25-7.3Bm,
2)1. Ar) Elemental analysis, calculated value CzvL. 07
: C, 69, 57; ) I, 8.05C, 69, 32
, H, 7,93 Actual value: 3→4 Compound 3 24.55g (49.1mmof) was added to 0.
It was dissolved in 1M hydrochloric acid/methanol solution and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (8/92 methanol/chloroform) to obtain 48.82 g (52.9%). A portion was crystallized using isopropyl ether.

Rf O, 32 (1/9 methanol/chloroform) Melting point (+wp, ) 52-54°C HNMR (CDC13+ CD30D) δ; 3.30 (
t, LH, J・9.46°H-6), 3.34(d,
LH, J=9.77, )l-1), 3.34(d,
LH.

J・9.46. H-3), 3.6Ht, IH,,L
=9.46), 3.71(t.

IN, J=9.46), 3.80(s, 3H,O
Me), 4.12 (br, s.

LH,)I-2), 4.28(dd, LH,J・5.
79.12.51), 4.38 (dd, 1) 1.
J・5.65.12.37), 4.59(d, LH
, J・1). 60CHzAr), 4.62(d, IH
, J=1). 29. C) IzAr), 5.17(d
d.

IH, J 1.22.10.37), 5.29 (dd,
LH, J = 1.5217.39), 5.98 (m,
IH), 6.87 (d, 2H, J=8.54.A
r), 7.29 (d, 2H, J=8.55. Ar)
Elemental analysis, calculated value C+Jz-Ot・'AHzO:C,
58,43; H,7,21 Actual value: C,5B,68, H,7,104→5 Compound 4 9.49 g (DM
Dissolved in F200-, 60% sodium hydride 5 under water cooling.
．． 6 g (139.5 mmol) was added at the same temperature.
After stirring for 0 minutes, 16.61 n of benzyl bromide was added at the same temperature! (
139.5 mmoj2) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with chloroform, the organic layer was washed with a sat. NaCl aqueous solution, and then anhydrous Mg5
Dry on. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (2,5/97.5 ethyl acetate/toluene) to give 15.74 g of 5 (80,6
%) was obtained. A portion was crystallized using isopropyl ether.

Rf3.33 (5/95 ethyl acetate/toluene)m
, p, 99-100'C'HNMR (CDCl 3'') δ; 3.27 (dd,
IH, J 2.23.9.80), 3.33 (dd,
IH, J・2.20.9.77), 3.4Ht, 18
．． , +=9.28) ,3.8Hs, 3H,OMe
), 3.92(t, 1)1. J=9.52)3.9
7 (t, IH, J・2.20.)I-2), 4.0
3 (t, IH, J・9.52) 4.30m, IH)
, 4.40 (m, 1) 1) , 4.52 (d, I
H, J=1). 23. C) IzAr) , 4.58(
d, 2H, J=12.94. CHzAr), 4.6
4(d, 1)1. J=1). 96. CLAr)
, 4.79-4.9Bm.

6H, CHzAr), 5.13 (m, LH), 5.
27 (n+, 1B), 5.98 (m, IH),
6.86-6.88 (m, 28.Ar), 7.24
-7.40 (m.

22H1^r) Elemental analysis, calculated value C-5H-1) 07:C,77,1
2: H, 6,90 Actual value: C, 77,00: H, 6,885 → 6 10.7 g (15,2 mmof) of compound 4 was dissolved in a mixed solution of 280 Idl acetonitrile and 7oIIi water,
Add 16.8 g (31 wool) of ceric ammonium nitrate (hereinafter abbreviated as cAN) under water cooling and stir at the same temperature for 1.5 hours. Ethyl acetate was added to the reaction solution, and washed with water, SAT, and NaCl2 water. and anhydrous Mg5O
.

After drying, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (8/92 ethyl acetate/toluene) to obtain 7.14 g (81%) of 6.

Rf O, 23 (1/9 ethyl acetate/toluene)'HN
MR(CDCj! riδ; 3.42(t, IH, J=
9.16), 3.44(dd, 1)1. J.
2.79. 9.94), 3.45(dd, IH,
J・2.79°9.76), 3.670. IH
, J・9.46), 4.02(t, IH, J・
9.76), 4.04(t, LH, J=2.6
0. H-2), 4.25 (+i, LH) 4.3
6(m, 1)1) , 4.66-5.02(i,
8H, CHzAr), 5.15(m, LH
) , 5.25 (m, LH) , 5.94 (m
, 18) , 7.157.38 (m, 20)
! , Ar) Elemental analysis, calculated value C3? H4゜0.・
1) 5) 1.0: C, 76,05; H, 6,9
7 Actual value: C, 76,04; H, 6,966 → 7 L-(+)-mandelic acid 8.2 g (53,8a+m
of) to acetyl chloride 10.75m (150.6mm
of) and stirred at room temperature for 50 minutes. Excess acetyl chloride was distilled off under reduced pressure at room temperature, and thionyl chloride 3 was added to the residue.
1 d (430 o + moj) was added and heated under reflux for 3 hours. Excess thionyl chloride was distilled off under reduced pressure at room temperature, and the residue was soaked in 200 d of a pyridine solution of 17,93 + uwol under water cooling at the same temperature. The reaction solution was stirred for 1 hour. Ethyl acetate was added to the reaction solution, and water and saturated NaCft were added.
After washing with water, it was dried over anhydrous Mg5Oa. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (2
/98 ethyl acetate/toluene) and then recrystallized twice from isopropyl alcohol.
g (17.6%) was obtained.

Rf O, 51 (1/9 ethyl acetate/toluene) m, p
, 1)7~1)8°C (α) D +31.6 (CO,25,CHCj!z
)'HNMR(CDCj2j)δ; 2.20(s,
3) 1.0Ac), 3.39(t, IH, J=9
．． 27), 3.49 (dd, LH, J=2.20.
9. ．． 77H-1), 3.84 (t, 18., y=
9.64), 4.00 (t, IH, J=9.52)
, 4.17 (t, IH, J=2.56. H-2)
, 4.61-4.91 (i+, 1)) 1), 5.27
-5.37 (m, IH), 5.85 (s, 18),
7.22-7.38 (m, 25)1. Ar) Elemental analysis, calculated value C4dlasOw: C, 74, 58;
H,6,39 Actual value: C,74,35; H,6,377→8 Compound 7 2.34 g (3,09 mmof) in TH
Flod was dissolved in a mixed solution of 40 II fl of methanol, 3.1 mmol of sodium methylate (28% methanol solution) (0.6 I1) was added at room temperature, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. was added and washed sequentially with sat, NaHcO, water, sat, and NaCl water, and then dried with anhydrous MgSO4.The residue was subjected to silica gel column chromatography (1/9 ethyl acetate/toluene), and 81.79 g (100%) I got it.

[α) D +10.1 (CO,91,CHCL)8
→9 Compound 8 1.78 g (3,07s + mojri D
MF5ON! 1, 231 ff1g (5.8m+*of) of 60% sodium hydride was added at room temperature, and after stirring at the same temperature for 20 minutes, methoxybenzyl chloride 0.
78d (5,8ma+ol) was added. After stirring at room temperature for 6 hours, the reaction solution was poured into ice water, extracted with chloroform, washed with saturated NaCl water, and dried over anhydrous MgSO4.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (2,5/97.5 ethyl acetate/toluene).
1.75 g (81%) of 9 was obtained.

[α]. +1.7 (cO,29,CHCl,) −
10 Compound 9 1.74 g (2,48 mrrlof) was dissolved in dimethyl sulfoxide 50H1, potassium ter
4.26 g (38 mmol) of -butoxide was added and stirred for 1.5 hours at 60°C under an argon (Ar) stream. The reaction solution was poured into ice water and extracted with chloroform.
After washing with sat, NaCj' water, it was dried with anhydrous FIgSOa. The solvent was distilled off under reduced pressure, and the residue had a concentration of 0. IN)ICj
7/C (1:9) 50% of the mixture was added and heated under reflux for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (5/95 ethyl acetate/toluene) and crystallized with n-hexane.
124 g (68.5%) were obtained.

Rf O, 28 (1/9 ethyl acetate/toluene),
p, 77-77.5°C [α]. +7.7° (c 0.22.CHCl ri'
HNMR (CDCl x) δ; 2.47 (s, IH
, OH), 3.16 (dd.

1) (, J・2.20.10.01.H-1), 3
．． 36 (t, LH, J・9.27°H-5), 3.3
7 (dd, IH, J・2.44.9.7?, H-3
), 8.81 (s, 3L OMe), 4.02 (t
, lH, J, 2.32. )l-2), 4.05(
t, l) I, J=9.52. H-6), 4
．． 15(br, t, 1B, J=9.52H
04), 4.42-4.92 (m, IOH, CHz
Ar), 6.85-6.87 (m2HAr), 7.
20-7.39 (m, 22H, Ar) elemental analysis, calculated value C4□H4,O,:C,76,33,H,6,7
1 Actual value: (:, ?6.14, H, 6,701-
12 Compound 1) 24.64 g (77.2 mmof) was dissolved in 700 d of acetonitrile, and 31.4 d of benzaldehyde dimethyl acecool (208,4+wa+oI
and p-)luenesulfonic acid 0.38 g (2 m
moffi) was added thereto, and the mixture was stirred overnight at room temperature under a nitrogen stream.

Triethylamine 21)i was added and the reaction solution was concentrated, ethyl acetate was added and 5atNaH (:03 water, 5atNaC
After sequentially washing with IH water, it was dried with anhydrous Mg5Oa. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (1/1O/90 triethylamine/ethyl acetate/
12 29.16g (92.8%
) was obtained.

Rf O,51 (1/9 ethyl acetate/toluene) (α
) o 40.0' (c 0.40.C) IC
j! 3)'HNMR(CDCl:l)δ; 0.1
6(s, 3L SiMe), 0.18(s,
3H, SiMe), 0.94(s, 9)1
．． 5itBu), 2.65(sIHOH), 3.
32 (dd, IH, J・7.63. 9.46.
H-2), 3.40 (ddd, 1) 1.
J・4.88. 9.15. 10.08. )I-
5), 3.56(t, II(, J=9.15.
)l-4), 3.63(dt, 1)1. J
=1.22. 9.46), 3.78(t, L
H, J=10.22. t(-6), 4.29(
dd, 1)1. J=5.03. 10.52.
H-6'), 4.65 (d 1) 1.
J=7.63. )I-1), 5.53(s, I
H, CHPh), 7.15-7.48 (m, 5H,
Ar).

Elemental analysis, calculated value C+ JzzC15N3SiC, 5
6,00; H, 7,17: N, 10.31
Actual value: (:, 56.13; H,?, 21;
N, 9.9512→13 Dissolve 29.0 g (71.2 mmoff) of compound 12 in THF600+Z and add 60% sodium hydride 4
．． Add 3 g (106.8 mmol) and heat for 60 minutes under Ar flow.
After stirring for 40 minutes at 'C, benzyl bromide 1)- was added and stirred at the same temperature. After 7.5 hours, the reaction solution was poured into ice water.
Extract the organic layer with ethyl acetate and satNac 1
After washing with 2 water, it was dried with anhydrous Mg5O. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (3
/7 n-hexane/toluene) and crystallized from n-hexane to obtain 27.78 g (78.5%) of 13.

Rf O,72 (2,5/97.5 ethyl acetate/toluene) m, p, 100-101 °C (α) n 84.5 (c O,91, CHCfs
)'HNMR(CDCf3)6; 0.15(s
, 3)1. SiMe), 0.16(s, 3H,
SiMe), 0.94 (s, 9H, 5itBu),
3.36 (dd.

IH, J 7.63.9.46. H-2), 3.38
(ddd, 1)1. J.4,889.46.10.
37. ) I-5) , 3.51 (t, IH, J=9
．． 46), 3.7Ht, Ill, J=9.46)
, 3.78 (t, IH, J, 10.37°H-6),
4.29 (ad, IH, J= 4.88.10.37
．． H-6'), 4.58 (d, IH, J=7.6
3. ) I-1), 4.78 (d, IH, J=1).
60°C)1. Ph), 4.90 (d, IH, J=1
). 29. CH, Ph), 5.56(s, 1N,
C) IPh), 7.25-7.48 (R1, 10f
l, Ar).

Elemental analysis, calculated values CzJxsN305Si:C,
62,75; H, 7,09; N, 8.44 Actual value: C, 62,74; H, 7,09; N,
8.3413=14a, 14b.

Compound 13 27.69g (55.7mmof) in T
Dissolved in HF600-, 56.9 g of borane-trimethylamine complex (779.8 mm) and molecular sieve 4A (hereinafter abbreviated as MS4A) 3
Add 0g of aluminum chloride and then add 104.1g of aluminum chloride under water cooling.
g (779.8 mmol) was added thereto, and the mixture was stirred overnight under an Ar stream. After adding 20 g of Amberlyst 15 and stirring for 10 minutes, suction filtration was performed, ethyl acetate was added to the filtrate, and the mixture was washed with water and satNaCII water. Then anhydrous Mg5
After drying with O, and distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (2,5/97.5 ethyl acetate/toluene) to obtain 30.6 g of 14a and 14b as a difficult-to-separate mixture. Obtained.

The above mixture was dissolved in 300 Ht of DMF, cooled with water, and 2 g of dazole (30 mmol, tert chloride)
-butyldimethylsilyl 4.5 g (30mmo6)
After stirring for 1 hour, water and ethyl acetate were added, and the organic layer was separated, washed with 5atNaCl1 water, and dried with anhydrous Mg5Oa. The residue was subjected to silica gel column chromatography (2/9
8 ethyl acetate/toluene), 14a 23.1
9 g (83.4%) were obtained.

Rf O, 37 (5/95 ethyl acetate/toluene) [
α) 6 31.67° (c O,42,CHCj!
3)'HNMR(CDCl3)δ; 0.16(,
s, 6H, SiMez), 0.94(s, 9H+
5itBu), 2.62 (d, 1B, J, 2.20
．． OH), 3.21 (dd, LH, J, 8.67,
9.89. Fl-3), 3.31 (dcf.

LH, J=7.69.9.89. H-2), 3.41
(dt, IH, J・9.53°4.89.H-5)
, 3.64(ddd, 1)1. J・2.20.8.
79°9.52. H-4), 3.7Hd, 2B,
J・4.89. H-6,6'), 4.53(d, I
H, J=7.57+H-1), 4.55(d, IH
, J.

1). 72. CHxPh), 4.59(d, IH
, J. 12.21. CH2Ph), 4.76 (d,
18. J.1). 48. C) IzPh), 4.9
1 (d, ILJ=1). 48. HzPh), 7
．． 25-7.40 (a, IOH, Ar).

Elemental analysis, calculated values CzJitNxOsSi:C,
62,50; H, 7,46: N, 8.41 Actual value: C, 62,19; H, 7,48, N, 8.
235-16 Compound @! 1) 24.9 g (46 mmoj2) of 5 was dissolved in 320 - of THF, and 13 d of acetic acid was added under water cooling. (230
Then, 140 yd of tetra-n-phthylammonium fluoride (IM in THF) was added and stirred at room temperature for 4 hours. To the reaction solution, water and ethyl acetate were added, and the organic layer was separated and washed with 5 at NaCl water. It was dried with anhydrous MgSO4. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (1/9 ethyl acetate/toluene) and crystallized with n-hexane.
6 18.58g (94.6%) was obtained.

Rf O, 47 (1/3 ethyl acetate/toluene)
'HNMR (CDCI,) δ; 1.83 (s, 0.
87)1. Ac), 1.86(s, 2.13!(,
Ac), 3.99 (t, 0.71H, J=9.64)
, 4.14(ddd, 0.71H, J=3.30.5
．． 86.10.01. H-5α), 4.5Hs, 2
8) , 4.56 (br, d, 0.29H, J=6
．． 62.1(-1β), 4.59-4.83(m,
2H, CHzPh), 5.00 (ddo, 71) 1.
J=9.28.10.25. H-4α), 5.3
Hbr, s.

0.71H, H-1α), 7.26-7.36(n+
, IOH, Ar).

Elemental analysis, calculation (l￥ C2□HzsNxOb :C
, 61, 81, H, 5, 90, N, 9.83 actual measurement (J
:C, 61, 66; )l, 5.96; N
, 9.8016→17 Compound 16 427K (1 mmof) in DMFIO/
Dissolved in d, tert-butyldiphenylsilyl chloride 1.04m (4o+mol), imidazole 408
(6 ml 1 ol) was added, and the mixture was stirred overnight at 60°C under an Ar stream. Ethyl acetate and water were added, and the organic layer was separated, washed with satNaCl water, and dried over anhydrous Mg5Oa. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (1/9 ethyl acetate/n-hexane).
and crystallized with n-hexane to give 17 474■
(71%) g.

Rf O,53 (1/6 ethyl acetate/n-hexane) a+, p, 77-78°C [α) o 16.25@(c O,4,CHCj
2:+)'HNMR(CDC43)δ; 1.12(s
, 98.5it-Bu), 1.80(s, 3H,
Ac), 3.13 (ddd, LH, J=3.96.
5.19°10.08. ) I-5) , 3.30 (t
, IH,J=9.46. H-3), 3.30 (dd
, LH,J=5.19.10.68. H-6), 3
．． 33(dd, 1)(, J=3.66, 10.68.
H-6'), 3.52 (dd, IH, J=7.
939.76, H-2), 4.25(d, 1B
, J=1). 90. CH! Ph), 4.3
0 (d, LH, J・1). 60. C)lzPh
), 4.39 (d, 1) 1°J・7.93.
Fl-1), 4.58 (d, IH, J・1). 2
9. HzPh) , 4.78(d, 1) 1
．． J.1). 29. HzPh), 4.9
8 (dd, IH.

J=9.31. 9.92. H-4), 7.13-
7.72 (m, 20)1. Ar).

Elemental analysis, calculated value C3m'daxNxOhS1:
C, 6B, 54; H, 6,51; N, 6°31 Actual measurement: (:, 68.74; H, 6,50
; N, 6.35”CNMR (CD (1/! 3)
; 96.82 (J・155.0) 17 → 18 Compound 17444 (0,667 smoj
Dissolved in a mixed solvent of IIi and methanol 101d,
0.1 d of 28% sodium methylate was added, and the mixture was stirred at room temperature overnight. Add ethyl acetate and water and separate the organic layer.
5atNacj! After washing with water, it was dried over anhydrous Mg5Oi.

After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (1/6 ethyl acetate/n-hexane),
18336■ (80.8%) was obtained.

Rf O, 28 (1/6 ethyl acetate/n-hexane) [α) o 1). 43° (c O, 21
,CHCl1z)'HNMR(CDCI,)δ; 1
．． IHs, 3H,5it-Bu), 2.53(
d, 18. J・2.45. OH), 2
．． 99(ddd, 1)1. J=4.57°4.
65. 9.77, H-5), 3.15 (dd,
IH, J=8.85. 9.77°■-3), 3.
43 (dd, LH, J・7.63. 9.76,
H-2), 3.43 (dd, LH, J・4.
57. 10.42. H-6), 3.49 (dd,
LHJ・4.58. 10.37. H-6'
), 3.64 (dt, IH, J・2.449°46. H-4), 4.36 (d, IH, J・1
2.20. CHzPh), 4.38(d,
1)1. J=7.94. H-1), 4.43(d
, IH, J=1). 90°CH! Ph), 4.75
(d, IH, J・1). 29. CH! Ph)
, 4.87 (d, IH, J=1). 60. C)
1. Ph), 7.19-7.71 (m, 20H, A
r).

Elemental analysis, calculation 4IiICiJa+N*05Si:
C, 69,31; H, 6,63; N, 6°7
4 Actual measurements: C, 69, 22; H, 6, 77, N,
6.4419→20 Compound 19 9.72 g (20 mmoj dissolved in 200 d of ethylene dichloride, tri-n-butyltin methyl sulfide 6.81) t1 (22 Q00 added, Ar
Stannous chloride 2.6yd (22tamo
1) and stirred at the same temperature for 3 hours. The reaction solution was poured into 5at NaHcO and water, and filtered through Celite.
The filtrate was washed successively with 5at NaHcOx water and 5atNaCl water, dried over anhydrous Mg5Oa, and the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (toluene-1/9 ethyl acetate/toluene) to give a concentration of 208.06
g (85.0%) was obtained.

Rf O,62 (1/3 ethyl acetate/toluene)
[α) D +53.14' (c O,35
, CHCl3)'HNMR(CDCl z)δ; 1.
97 (s, 3H), 2.06 (s, 3H), 2.
12(s, 3H), 3.96(t, LH, J=9
．． 46) 1-4), 3.97 (dd, IH, J.
1.83.3.36. ) I-2) , 4.2Hdt,
LH.

J・3.66, 9.77, H-5), 4.33(d,
2H, J=3.66, H6,6'), 4.5Hd
, IH,J=12.20. CH2Ph), 4.5
8 (d, IH, J・12.21.CH2Ph),
4.68 (d, IH, J・12.21°C) 1. Ph
), 4.69(d, 1)1. J, 1). 30. C
)1. Ph), 5.18 (dd, IH, J=3.3
6.9.46.8-3), 5.24(d, 1)1.
J・1.53. H-3), 7.25-7.34 (a
+, 10H, Ar).

Elemental analysis, calculated value CZSH3゜07S:C,63,2
8: H, 6°37 Actual value: C, 63,01; H, 6,42" CNMR
(CDCff); 82.95 (J・167.
2) 21→22 Compound 21 3.2 g (6a+oof) in DMF4
1.1 g of hydrazine acetate (12++n
of) was added and stirred at room temperature for 2 hours. Diethyl ether and water were added, and the organic layer was separated, washed successively with water and satNaCl, dried over anhydrous Mg5Oa, and the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (1/2 ethyl acetate/n-hexane) to yield 222.21 g (7
4.8%).

Rf O,3(1/2 ethyl acetate/n-hexane)')INMR(CD13)δ; 2.03(s, 0
．． 81H, Ac), 2.04 (s.

2.19H, AC), 3.50(ddd, 0.27H
, J-2, 20, 5, 86°9.53. H-5β)
, 3.64 (dd, 0.27H, J・3.1). 9.
71°H-3β), 3.8Hdd, 0.73H,J
・1.91.2.27. H-2α), 3.92(t
, 0.73H, J=9.34. H-4α), 3.
98 (dd, 0.73H, J・2.93.9.16.
)! -3α), 4.02(addO,73H,J=
1.83.5.13.9.53. H~5α), 4.
23(ddO,27H,5,67,1),90,H-6
β), 4.26 (dd, 0.73H.

J・5.13.12.09. H-6α), 4°37(
dd, 0.27H, J=2.20.1). 72. H
-6' β), 4.38 (dd, 0.73)1.
J・2.02. 1). 91. H-6' cr)
, 4.58-5. IHm, 6B.

C) I, Ph), 5.24 (dd, 0.73H, J
・1.83. 3.30. H-1α), 7.25-
7.37(n+, 15)1. Ar).

Elemental analysis, calculated value CzqHzO7・”A H20:
C,70,07; H6,59 Actual value: C,70,03; H,6,6122→23 Compound 22492 (1 mmol) was dissolved in 10-ethylene dichloride and heated at -23°C under an Ar flow. Diethylaminosulfur trifluoride (hereinafter abbreviated as DAST)
) 0.16d (add 1st and 2nd stage Akebono 00, 4 at room temperature
The reaction solution stirred for 0 minutes was poured into 5atNa)ICOs water, extracted with chloroform, washed with 5atNaCIH water, and dried over anhydrous Mg5O. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (1)
5 ethyl acetate/n-hexane> to give 23449 (
90.9%) was obtained.

Rf O,42 (1/4 ethyl acetate/n-hexane) (α) n +29.22° (c 1.42.
CHCl3)'IINMR(CDC1s)δ; 2.
05(s, 3H, Ac), 4.27(dd.

1)1. J・4.89. 12.58. )I-
4), 4.37 (dd, 18. J.

1.83. 1). 91. H-3), 4.59-
4.93 (+s, 6H, CHzPh), 5.55
(dd, 1)1. J・1.84. 50.56
．． H-1), 7.15-7.35 (m, 15H
, Ar).

” CNMR (CDCi's) δ: 101.32
(J・183.1) Elemental analysis, calculated value CzJi+FO
b: C, 70, 43; H, 6, 32 Actual value: C, ? 0.31; H, 6,3924→2
5 Compound 24 19.5 mg (50 mmoo) was dissolved in 500 mm of ethylene dichloride, then 9.3 g of hydroquinone monomethyl ether (75 n+moj) was added, and A
Add 2.9 m (15 au+of) of trimethylsilyl trifluoromethanesulfonate at -15°C under r air flow,
The 0 reaction solution stirred at room temperature for 3 hours was diluted with 5atNaHcO.
3 Pour into water and extract with chloroform, 5atNaCj
! After washing with water, it was dried over anhydrous Mg5Oa. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (1
/2 ethyl acetate/n-hexane), 25 19.
9g (87.7%) was obtained.

Rf O,24 (1/2 ethyl acetate/n-hexane) (α) n + 9.63” (c O,5
4.CHCj? z)'HNMR (CDCI δ; 2
．． OHs, 3H, Ac), 2.05 (s.

3H, Ac), 2.08(s, 3)1. Ac)
, 2.18 (s, 3H, Ac), 3°? ? (s, 3
L OMe), 4.00 (dt, IL J=1.22
．． 6.71°H-5), 4.16(dd, IH, J=
6.71.1). 29. H-6), 4.23 (dd,
IH, J.7.01.1). 29. Fl-6')
, 4.91 (d, IFI.

J, 8.24. )l-1), 5.09(dd, 1)
1. J, 3.51.10.53. H-3), 5.4
4(dd, 1)(, J・0.92.3.36.ll
-4), 5.45 (dd, 18. J=7.93.
10.37. Fl-2′), 6.80-6.97(
*, 4H, Ar).

"CNMR (CD(13)δ; 100.937 (
J, 162.35) Elemental analysis, calculated value Cz+LJz
・'A)IzO;C,54,95;)I,
5.82 actual measurement: (, 54, 69; H, 5,
8125→26 19.8 g (43.6 mmol) of compound 25 was dissolved in 200 methanol, and sodium methylate (28
% methanol solution) 2d (10 mmoj?) was added and stirred at room temperature for 1 hour. After neutralizing by adding Amberlyst 15 and filtering the solid matter, the solvent was distilled off under reduced pressure.26 1)
．． 62 g (93.2%) were obtained.

A portion was recrystallized from methanol.

Rf O,42 (2/8 methanol/chloroform)
Faith, p, 160-161℃ [α) o 41.79° (c O, 2B, M
eO)1)'l(NMR(CDCj'3 +CDzOD
) δ: 3.7? (s, 3)f, OMe), 3.9
7 (d, IH, J = 1.84. H-4), 4.75
(d, LH, J・7.93°H-13,6,81-7
, 05 (m, 4H, At).

Elemental analysis, calculated value C+J+sOt ・I/3) 1zo
;C,53,42;H6,43 Actual value:C,53,54,)I, 6.3126→27 Compound 26 1). 6 g (40.55 mmoj) was dissolved in anhydrous pyridine 250R1, and 19.5 g (57
, 47 mmol) and stirred overnight at room temperature, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure.
Ethyl acetate and water were added, and the organic layer was separated and washed with 5at NaCl water. After drying with anhydrous Mg5O, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (1/2
/98) diethylamine/methanol/chloroform)
21.55 g of 27 (90.3%) was obtained.

Rf 0.51 (2/8 methanol/chloroform) [α), -22,32° (c O,56,C
HCl 3)'HNMR (CDCl s ) δ;
3.38 (dd, IN, J=5.04°9.92.
H-6), 3.50 (dd, LH, J・6.10.
10.0? , H-6'), 3.63 (br, t,
IH, J=5.80. H-5), 3.75(s,
38. OMe), 3.77(s, 68.OMe)
, 3.88 (dd, IH, J, 7.63.9.46°H-2), 3.99 (br, s, IH, H-4),
4.73 (d, IH, J = 7.63°) 1-1), 6
．． 79-7.44 (m, 17B, Ar).

Elemental analysis, calculated value C5aHsbOya: C, 69, 3
7; H, 6,16 Actual value: C, 68,99; H, 6,5127→28 Compound 27 21.5 g (36,5 mmof) to D
5.85 g (146.3 mmof) of 760% sodium hydride dissolved in MF500II and ice-cooled in a stream of Ar
was added and stirred for 1 hour, then 15.6 d of benzyl bromide
(128 mmol) was added and stirred at room temperature for 2 days.

Pour the reaction solution into ice water and extract with diethyl ether? After washing with 5at NaCFl water, it was dried with anhydrous MgS.

The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in chloroform 420
m1. The mixture was dissolved in a mixed solvent of 180 μm of methanol, 300 μm of p-)luenesulfonic acid was added, and the mixture was stirred at room temperature for 30 minutes.

The reaction solution was poured into 5atNaHcI]z water, and the organic layer was separated, washed with 5atNaCl and dried with anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (1/9 ethyl acetate/toluene).
8 13.45g (66.3%) was obtained.

Rf O,25 (2/8 ethyl acetate/toluene) [α
]o 24.76° (CO, 21, C) ICL)
'HNMR (CDCI!3) δ; 3.48 (b
r, t, It(, J=5.49°H-5), 3.50
(ddd, l)I, J=5.13.8.79.1)
], 99.8-6), 3.61 (dd, IH, J=2
．． 93.9.52. )(-3), 3.76(S,
3H.

OMe), 3.82(d, 1)1. J=2.56.
8-4), 4.10 (dd, IH.

J Near, 69. 9.89. 1(-2), 4.67
-4.87 (m, 4H, CLPh), 4.8
8 (d, ill, J=8.06.H-1), 4.
99(d, 1)1. J=12.45゜CH2Ph)
,5. OHd, IH, J=1). 36. C)I
ZPh), 6.797.00(m, 4H, Ar
), 7.26-7.40 (n+, 15) 1.
Ar).

Elemental analysis, calculated value CxaHxh07'C,? 3.36
, H, 6,52 Actual value: C, 73, 23, H, 6, 5118 + 20 → 2
9 20 g pre-dried MS 4A, 4.5 cupric bromide
8 g (20,5m5sol), 0.92 g (2,85mmoff) of tetra-n-butylammonium bromide
) and trifluorosulfone (mmol)) under an Ar atmosphere, a nitromethane solution of 5.96 g (12.5 s+mol) of 1501R1 in nitromethane was added at room temperature, and the mixture was stirred overnight at the same temperature. did. After making the reaction solution basic by adding triethyl alcohol, it was filtered through Celite, and ethyl acetate was added to the filtrate to dissolve satNaHcO3 water, water, satNaC
1 and washed sequentially with water. After drying anhydrous MgSOa, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (5/95 ethyl acetate/toluene).
5g (85.7%) was obtained.

Rf 0.7 (1/9 ethyl acetate/toluene) (
α) D +4.1” (c O.34. C
HCi'+)HNMR (CDC1s) δ
; 1.12(s, 9)1, SitBu),
1.92 (s. 3) 1, Ac), 1.94
(s. 3H, Ac), 2.99 (ddd,
LH.

J・1.53. 4.28, 9.77, H-
5b), 3.28(dd, IH J=9,0
0, 9.92. R-3b), 3.39(d
d, IH, J=1.68.

1), 14, H-6b), 3.49(dd, 1
)1, J=7.78, 9.92, H-2b
), 3.53 (bd, 1) 1. J=4.42.
1). 14, H-6' b), 3, 70 (t
, 1) 1, J=2.75, H-2c)
, 3.79 (t, IH, J-9, 31, H-
4b), 3.79 (ddd, IH. J=2.74
, 4.27.

9, 77, )! -5c), 3.86 (t.
IH, J=9.31, H-4c), 4,0
5 (d, IH, CH2Ph), 4.12-4.18 (n
+, 2H, H-6.6' c), 4, 14(d
, 1) 1, J=12.20. HzPh)
, 4.3Hd, LH, J・1), 67,
HzPh), 4.34(d, IH, J
=1). 67, C) IZPh), 4, 38 (d
, 1) 1, J=7.93, H-1b)
, 4.5Hd, 1) (, J=1), 29,
CH2Ph), 4.63 (d, IH, J.
1). 29, C) 12Ph), 4, 64 (d.
LH, J=1). 30. HzPh)
, 4.97(d, 1)t, J・1), 30.
HzPh), 5.13(dd, IH,
J・3.05, 8.85.

H-3c), 5.22(d, 1)(, J=
2.14, )l-1c), 7.08-7.73
(m, 30H, Ar).

"CNMR (CDCl3)δ; 96.89
(J.158.7.C-1b), 99, 42
(J.172.1, C-1c).

Elemental analysis, calculated value C. )IiJholzSi :C
, 68.61; H, 6.43;
N, 4.00 Actual value: C, 68.64;
H, 6.45, N, 4.0129→30 Compound 29525■ (0.5 mmof) in THFI5
Dissolve in water and cool under ice to reduce acidity. 2 4 d (4.
0 mmoj, then tetra-n-butylammonium fluoride (LM THF solution)2. OId was added and the mixture was stirred at room temperature overnight. Add ethyl acetate to the reaction solution and add HtO
After washing with satNaCl water, the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (2/8 ethyl acetate/toluene) to give 30391 (96%)
I got it.

RtO. 22 (2/8 ethyl acetate/toluene)'
HNMR (CDCi δ; 5.24 (dd
, 0.59H. J・2.90.

8, 70. 8-3c), 5.34(t, 0.59
H, J=3.51, H-1bα).

Elemental analysis, calculated value Ca4HaJ4sO+z:C,
65.01; H, 6.08; N, 5.
18 Actual value: (:, 65.06; H, 6.1
8; N, 5.0530→31 Compound 30 3 7 5++g (0.4 6 m
o+ol) was dissolved in 10M1 of ethylene dichloride and DAST 7 3 1! 1 (0.
5 mm of water was added, and the mixture was stirred at room temperature for 30 minutes. Pour the reaction solution into ice water, separate the organic layer, and add satNa
After washing with C12 water, it was dried with anhydrous MgSOn. The residue was subjected to silica gel column chromatography (1/9 ethyl acetate/toluene) to obtain 33375 (quantitative).

Rf O. 44 (1/9 ethyl acetate/toluene)'
HNMR (CDCj!s)δ. 5.1) (dd,
0.66H, J=6.97.

52, 39, H-1bβ), 5.25 (dd,
0.34H. J.3.298, 42. 8-3c)
, 5.68 (dd, 0.34H, J・2.20.
52.75.

)1-1bα).

Elemental analysis, calculated value CaaH4aFNsOx:C,
64.93; l(, 5.95; N, 5
．． 16 Actual value: C, 64.91: H, 6.0
0; N, 5.0631+10-32 1.2 g of pre-dried MS4A, biscyclopentadienyldichlorozirconium 857+ag (2,93 m
+moj and silver perchlorate 608■ (2,93 mmo
15 d of an anhydrous diethyl ether solution of Compound 31 596 mg (0,733 mmoffi) and Compound 10300 (0,455 m++ mof) were added to the reaction vessel containing f) at O''C under an Ar flow, and the mixture was stirred overnight at room temperature. Triethylamine was added to the reaction solution to make it basic, and insoluble materials were filtered through Celite.Ethyl acetate was added to the filtrate, and the mixture was washed successively with saturated NaHCOz water and 5atNaCl water.

Then, after drying over anhydrous MgO, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (5/95 acetone/toluene) to obtain 32480mm (72.7%
) and the β-isomer 130 μ (19.7%) were obtained.

32 Rt O,6 (5/95 acetone/toluene) (α) o +49.2' (c O,6,CHC
l! , z)' HNMR (CDCf s) 500M)
Iz, δ; 1.92 (s, 3)1. Ac
), 1.96 (s, 3H, Ac), 3.19 (dd
, LH, J=3.66, 10.37°H-2b),
3.26 (dd, 1)1. J=2.14.10.0
7. H-1a or3a), 3.36(dd,
IH, J=2.29. 9.92. H-1a o
r 3a), 3.42-3.46 (a+, 28.
)I-6,6' b), 3.57(t, IH,
J=9°15), 3.62 (s, 3H, OMe),
3.73 (dt, IH, J=3.20°9.76,
H-5b), 3.73(t, LH, J=2
．． 59. H-2c), 3.85(t, LH
, J・9.46), 3.9Ht, 1)1.
J・9.16), 3.93(t, 1)1.
J=9.00), 3.98(br, s, IH,
H-2a), 3.99 (d, LH, J・12.81
．． CH, Ph), 4.07(d, 1)1.
J・10.68. HzPh), 4.09
(t, 1)1. J=9.15), 4.09
-4.17 (m, 2) 1. H-6,6' c)
, 4.29 (t, IL J=9.62) , 4
．． 37 (br, d, LH, H-9, 77, H-5c
), 4.39-5.06 (m.

16H, CHzPh), 5.19(d, 1H,
J=2.13. 8-1c), 5.29(dd,
1)1. J=3.05. 9.46. H3c
), 5.60 (d, 1) 1°J=3.66,
H-1b), 6.83(d, 21). J
=8.55. Ar), 7.07-7.36 (+++
, 42H, Ar).

3CNMR(CDC41!*)δ, 97.63
(J=177.0.C-1b), 100.28
(J=172.1.C-1c).

Elemental analysis, calculated value CeJq1NiO4:C, 71,0
0; H, 6, 31; N, 2.89 Actual value: C
,70,70,H,6,31; N, 2.73β-
Isomer Rf 0.67 (5/95 acetone/toluene) [
α) o + 6.7° (c O,82,CHC
l 3)'HNMR (CDCl 3) 500MH2, δ
; 1.94 (s, 6H, Ac), 3.28 (
dd, I)1. J・8.85. 9.76),
3.35 (dd, IH, J・2.29. 9.9
2. H-1a or H-3a), 3.37(
dd, 1)1. J=8.08. 9.91.
H-2b), 3.39-3.69(m, 1B
), 3.41 (dd, LH, J=2.14.9.
77, ) f-1a or ) 13a) , 3.4
5 (t, IH, J・9.15), 3.62 (d
d, IH, J・5.01. 12.42゜H-6b
), 3.71 (t, IH, J=9.15)
, 3.75 (L, LH, J=2.75. H-2
c) , 3.80-3.82 (+++, 18),
3.82(s, 3H.

OMe), 3.84 (t II (, J, 8.24)
, 3.89 (ddd, IH, J.

1.83. 4.5B, 9.77, H5c),
3.99 (br, s, DI, H-2a), 4.
04(t, IH, J=9.46), 4.07(
d, I) I, J, 1). 59°CHtPh),
4.14 (dd, 1)1. J=4.88. 1
). 90. H-6c), 4.16(d, I
H, J, 1). 90. CI(!Ph), 4.2
0 (dd, 18J・1.83.1). 90.
)! -6'c), 4.34(d, Ill, J
=1). 90°CHtPh), 4.40(t, IH
, J-9, 31), 4.45-4.85 (m.

13H, CHtPh), 4.96(d, IH,
J・7.93. H-1b), 4.98(d,
IH, J・1). 29. CHzPh), 5.
01(d, 1) [, J・1). 29. CHzP
h), 5.19 (d, IH, J=2.14.
H-1c), 5.22 (dd, IH, J=2
．． 90. 8.39. H-3c), 6.9Hd
2H.

J-8,55,Ar), 7.09-7.35(m,
428. Ar).

'3CNMR (CDC13) δ: 99.94
(J=171.6.C-1c), 101.52
(J=165.9.C-1b).

Actual value: C,? 1.28; H, 6,45; N
, 2.53°32→33 Compound 32 48 Qmg (0.33m5of) T
HF5IIIi! The mixture was dissolved in a mixed solvent of 10 - methanol, 0.13 ml of sodium methylate (28% methanol solution) was added at room temperature, and the mixture was stirred for 5 hours. Ambaris)
15 was added to neutralize the mixture, insoluble materials were filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (l/
9 (ethyl acetate/toluene) to give 33452 (quantitative).

Rf O,1B (1/9 ethyl acetate/toluene) [
αE, +54.25° (c 5.55.CHCf
3)'HN phylum R (CDCl 3) δ; 3.21 (d
d, III, J・3.66, 9.76°H-2b)
, 3.28 (dd, 18. J=1.98.9.9
2), 3.43 (dd.

II (, J=2.44.1). 60. )l-6b),
3.59(t, 1)1. J=9.31), 3.6H
t, 1B, J=9.31), 3.65(s, 3
H, OMe), 3.87 (t, 1) 1. J.9.
16), 3.89(t, 1)1. J=9.4
6), 3.99(d, 1)f, J・1). 29
．． C)1. Ph), 4.09(t, 1)1.
J=9.46), 4.13(d, LH, J=1
). 59. CHzPh), 4.26(br, d,
LH.

J・9.77', H-5c), 4.3Ht, LH,
J・9.61), 4.38--5.08 (pull 16
1). CLPh), 5.28 (d, IH, J・1
．． 52. Hlc), 5.61(d, IH, J.
3.66, H-1b), 6.81-7.39(
m, 44H, Ar).

Elemental analysis, calculated value C5JstN3014:C,? 1
．． 86; H, 6, 40, N, 3.07 actual value I
C,72,04;)I,6.48;N,
2.803-34 Compound 33 66w (0,048 mmol) was dissolved in pyridine 2-, and acetyl chloride 0.014 mf (
0.196 wmoj of water was added and stirred at the same temperature for 7 hours. After methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (1/9 ethyl acetate/toluene) to obtain 3464* (94.5%).

Rf O,24 (1/9 ethyl acetate/toluene) [α
]. +69.34 @(c O,61,CHClz)'
HNMR(CDCj2:I)δ; 1.92(s
, 3H, Ac), 3.23 (dd.

1)1. J・3.66, 10.07. Fl-
2b) , 3.28 (dd, IH, J=2.14
．． 10.07), 3.37(dd, 1)1.
J・2.14. 9.76), 3.43(d, 28
．． J・2.13. H-6,6' b), 3.5
8(t, 2)IJ=9.30), 3.66(s
, 3H, OMe), 3.84(t, 1) [J.

9.31), 3.88(t, IH, J・9.9
2), 3.95(d, 1)1. J.1).
59. HzPh), 3.97(br, s,
IH,)l-2a), 4.09(t, IH,J=
9.46), 4.14(d, 2F[, J.3.
35. Fl-66'c), 4.15(d, 18
．． J□10.98. CJPh), 4.29
(br, d, 1)1. J=9.79. H-
5c), 4.33 (t, 18. J=9.61)
, 4.38-5.08 (m, 16) 1. C
LPh), 5.27(d, 1)f, J=1.2
2°H-1c), 5.64(d, IH, J=3
．． 66, H-1b), 6.8Hd.

2H, J=8.54. Ar), 7.05-7.
39 (n+, 428. Ar).

Elemental analysis, calculated value C5JsJzO+t: C, 71,
42; H, 6, 35; N, 2.97 Actual value:
C, 71,42: H, 6,37; N, 2.9
835+28→36 15g pre-dried MS4A, cupric bromide 4.46
g (20 mmof) and 6.44 g (20 mmoi) of tetra-n-butylammonium bromide were placed in a container containing 35 6.84 g (12 mmof) and 2
85.56 g (10 mmoJ) of ethylene dichloride8
31n! , a solution of DMF16.5- was added under an Ar flow,
The mixture was stirred overnight at room temperature. After making it basic by adding triethylamine, it was filtered through Celite. Chloroform was added to the filtrate, which was washed successively with 5atNa)ICOz water and 5atNaCl water, and dried over anhydrous Mg5Oa. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (2,5
/97.5 ethyl acetate/toluene), 36 7.
27 g (67.4%) were obtained. A portion was recrystallized from isopropyl ether.

Rf O, 48 (1/9 ethyl acetate/toluene) Peng,
p, 126-127°C [α) D +17.7° (c O, 35, CHCl
3)'HNMR(CDCj! 3)δ; 3.46(
dd, IH, J・5.86.9.89), 3.50(c
l, 2H, J・6.96), 3.57(dd, 1
)1. J, 2.93°9.89. H-3f), 3
．． 67(s, 38.OMe), 3.65-3.68
(m.

IH), 3°81-3.84 (m, 2H), 3.87
(dd, LH, J・2.74゜10.07.) l-
3g), 3.89-3.91(s+, 2)1), 4.
0Hdd, IH.

J=3.48.10.08. H-2g), 4.05(
dd, LH, J・7.88°9.72. H-2f
), 4.32-4.99 (m, 14HCHzP
h>, 4.73 (d, LH, J・3.30.H
lb), 4.82 (d, LH, J・7.70.
H-If), 6.73 (dd, 1) 1. J
=2.20. 6.60. Ar), 7.00 (dd
, 1B, J=2.20. 6.96. Ar
), 7.01-7.38 (Ill, 35H).

"CNMR(CDCf3)δ, 98.22
(J・169.67, C-1g), 103.1
(J=161.13.C-1f).

C65H7oO+z: ; H,6,54; H,6,53 Elemental analysis, calculated value C,75,67 Actual value: C,75,31 36→37 Compound 362.25■ (2sno l) was dissolved in toluene 2
Ceric ammonium nitrate was dissolved in a mixed solvent of 4M1, 30d of acetonitrile, and 15% of water at 0°C.
．． Ethyl acetate was added to the reaction solution, which was stirred for 10 minutes after adding 5 g (10 tao It), and mixed with water and 5aLNac1.
After washing with water and drying with anhydrous Mg5Oa, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (1/
9 ethyl acetate/toluene), 37 1.27g
(65.2%) was obtained.

Rf O, 15 (1/9 ethyl acetate/toluene) elemental analysis, calculated value CHI) 1640+1 ・'A H20
C, 74,59; H, 6,57 Actual value: C, 74,35; H, 6,6237 → 38 Compound 37250 (0,256a+mof) was converted to ethylene dichloride 51) 1)! Dissolved in 70.04ml of DAS at -23°C under Ar flow! (0.3n+of) was added and stirred at room temperature for 0.5 hours. The reaction solution was poured into ice water.
Chloroform extraction was performed, followed by 5atNaHcO,
After sequentially washing with water and 5at NaCl, it was dried with anhydrous Mg5O. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (5/95 ethyl acetate/toluene) to obtain 38241 (96%).

Rf O, 66 (1/9 ethyl acetate/toluene)'H
NMR (CDCj!ri 6; 5.10 (dd,
0.6H, J, 7.02°53.10. )I-1fβ
), 5.55 (dd, 0.4H, J=2.59゜5
4.17. H-1fα).

Elemental analysis, calculated values: C, 75,13, H, 6,51 actual measurements (I!: C, 75,18; H, 6,4934+
38 → 39 Pre-dried MS4A200■, biscyclopentadienyldichlorozirconium 124■ (0,425mn
+of) and silver perchlorate 88■ (0,425mmof)
) in a container containing 34 to 60 ■ (
0,0425mmof) hyohi38 831g (0
, 085taraol) f) Di:r-chillny 7-l solution 51) 1 was added and stirred for 4 hours. Triethyl atrione was added to the reaction solution to make it basic, insoluble matter was filtered through Celite, and ethyl acetate was added to the filtrate. Add 5 at NaHCO.

Water, satNaCI! Anhydrous MgSO4 after sequential washing with water
It was dried. After evaporating the solvent under reduced pressure, the residue was purified by preparative TLC (3/In-hexane/ethyl acetate) (1
8%).

'HNMR(CDCI!,,)δ; 1.82(s,
3H, Ac), 3.18 (dd.

IH, J=3.67, 10.07. )l-2b), 3
．． 22 (dd, IH, J.

1.98.9.92), 3.48(s, 3H,OM
e), 5.24 (br, sIH, H-1c), 5.6
3 (d, LH, J=3.67, H-1b), 6.
77 (d, 2H, J=8.54.Ar), 7.1
3-7.36 (sr, 77)1. Ar).

I3CNMR (CDCj!3) 6; 97.63
(,1=175.8.C-1b),98.93 (
J=169.7. C-1g), 99.37 (
J=169.7. C-1f), 99.91
(J=166, C-1c).

Elemental analysis, calculated value C+asH+s+Nx0zt ・y
2HzO:C,? 3.27; H, 6,44;
N 1.77 Actual value: (:, ?3.00;
H, 6,40; N, 1.6046 Rf O
,4(1/3 ethyl acetate/n-hexane)'HNMR(
CDCL) δ; 1.845 (s, 3H, Ac)
, 3.504(s, 3)1. OMe), 5.13
6 (d, IH, J=3.05.H-1d), 5.
392 (d, 1) (, J-1, 83, H-1c), 5
．． 621 (d, IH, J.

3.67, 1(-1b), 6.814(d, 2
LJ=8.54. Ar), 7.085-7.36
7 (■, 62H, aromatic proton).

39→40 Compound 39 136Mg (0,057smoj T
It was dissolved in a mixed solvent of HF2- and methanol (4jlf), and 46μi of sodium methylate (28% methanol solution) was added at room temperature, followed by stirring for 5 hours. Next, Amberlis 1-15 was added to neutralize the mixture, and insoluble matter was filtered out, and the solvent was distilled off under reduced pressure. The residue was purified by Preparatif TLC (1/9 ethyl acetate/toluene) to obtain 401)8 (89%).

Rf O,46 (1/9 ethyl acetate/toluene) (α
) n +63.0' (c O,36,CHCj!
'HNMR (CDCI) δ; 3.47 (s,
31(,OMe), 5.28(br,sr IH,H
-1c), 5.58(d, IH,, r=3.67+
H-1b), 6.74 (d, 2) 1. J=8.06
．． Ar), 7.09-7.40 (m, 77B.

Ar).

Elemental analysis, calculated value CBJ+aJsOza: C, 7
3,85; H, 6,45; N, 1.81 actual measurement 4WL: C, 73,71; H, 6,47; N,
1.7040+41→42 Pre-dried MS4A500■, mercuric bromide 61
rz (0,17a+a+oA') and 1!128■ of cyanide water (0,5smog), add A
Compound 40 98+w (0,042
+ wmol) of ethylene dichloride solution 5W1) was added, and then 3M1 of compound 41 86sir (0.17 mmol) of ethylene dichloride solution was added and stirred overnight at room temperature. Triethylamine was added to the reaction solution to make it basic and remove insoluble matter. was filtered through Celite, and chloroform was added to the filtrate. 5a
It was washed sequentially with tNaHcO3 water and satNaCl water. The residue was then dried over anhydrous Mg5O, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (1/9 ethyl acetate/toluene) to obtain 42105 (89%).

Rf O,54 (1/9 ethyl acetate/toluene) [α
) D + 73.2” (c O,57,CHCl3
)'HNMR(CDCl3)δ; 2.05(s
, 3H, Ac), 3.18 (dd.

IH, J=4°03. 10.25. H-2b),
3.20 (dd, IHJ・1.83.9.89)
, 3.45 (s, 3)1. OMe), 5.
24(d, IH.

J=1.09. H-1c), 5.32(d,
1)1. J=1.47. H4b), 5.
38 (d, IH, J・1.84.H-1f)
, 5.39 (dd, 1) 1. J=1.83.
3.29. H-2d), 5.6Hd, 1
)(, J・3.66, H-1b), 6.78(
d, 2H, J=8.43. Ar), 7.0
3-7.34 (m, 92H.

Ar).

+3cs phylum R (CDC13) δ; 97.66
(, J=176.1.C-1b), 98.23
(J=170.7.C-1g), 98.53
(J=172.1.C-1d), 99.38
(J=168.5.C-1f), 100.
3 (C-1c).

Elemental analysis, calculated value C+tz)1+tJ30+□・1)
5C) IC7!3°C, 73, 23; ) I, 6
．． 40; N, 1.49 Actual value: (:, ?
3.32; H, 6,68, N, 1.432-4
3 Compound 42 225N (0.08 mmoj in THF
Sodium methylate (28% methanol solution) 4- dissolved in a mixed solvent of 4- and methanol 6- at room temperature.
Added 8 μl and stirred for 5 hours.
was added to neutralize the mixture, insoluble materials were filtered out, and the solvent was distilled off under reduced pressure.

The residue was purified by preparative TLC (1/9 ethyl acetate/toluene) to obtain 43207 (93.6%).

Rf O, 1g (1/9 ethyl acetate/toluene) [
α〕. +72.9 @(cO,55,CHCl3)
'HNMR (CDCI ri δ; 3.18 (dd,
IH, J・3.66, 10.26°) 1-2b), 3
．． 21 (dd, IH, J=1.83.9.89), 3
．． 45 (s.

3H, OMe), 5.3Hd, 1)1. J=1.8
3. H-1f), 5.63 (dIH, J=3.67
, H-1b) , 6.77 (d, 2H, J=8.4
3. Ar), 7.05-7.35 (a+, 92)1
．． Ar).

'3CNMR (CDC1s) δ; 97.66 (
J.177.2. C-1b), 98.45 (J・1
68.8), 99.32 (J, 168.8), 9
9.79 (J・167.4), 100.14 (
J=163.1).

Elemental analysis, calculated value C+t. HI□7N, 0□ :C,
74,02; H, 6,47; N, 1.52
Actual value: (:, 73.38; )I, 6.53
; N, 1.4843+23-44 pre-dried MS4A200■, biscyclopentagenyl dichlorozirconium 58.5■ (0.2 mmo
l) and 41.5qr silver perchlorate (0,2solo
Compound 43 was added to a container containing 1) at room temperature under an Ar flow.
27.61) 1r (0,01 mmoj+) and Compound 23 19,8 N (0,04a+moj) of diethyl ether solution 5- were added and stirred overnight. The 0 reaction solution was made basic by adding triethylamine, and the insoluble matter was poured into Celite. Filter, add ethyl acetate to the filtrate and add 5atNaHcO.
: + water, anhydrous Mg5O after sequentially washing with 5at NaCl water,
It was dried. After evaporating the solvent under reduced pressure, the residue was purified by preparative TLC (1/9 ethyl acetate/toluene),
4430■ (92,9%) and 492■ (6,2%)
I got it.

44 Rf O,73 (1/9 ethyl acetate/toluene) [αE tr 1,50.97” (CO,31
, CHCl3)') INMR (C4D6.60°C) δ;
1.76 (s, 3H, Ac), 3.15 (dd
, 18. J・3.66, 10.37. H-2
b), 3.22 (dd, 1) 1°J = 2.29.9
．． 92), 3.27 (da, IH, J=2.1
4. 10.08), 3.40(s, 3H,OM
e), 3.59 (br, d, 1)1. J=9.
77), 3.64 (dd, IH, J・5.80.
9.16), 3.67(b, 1)1. J・9.0
0), 5.03(d, 18. J=3.67
, t(-1g), 5.19(d.

1)1. J・1.83), 5.23(d, I
H, J = 1.83), 5.38 (d.

LH, J=3.36. 1l-If), 5.78(
d, Ill, J・1.83), 5.87(
d, IH, J=3.66, 8-1b), 6.
98-7.53 (m, 109H9^rL" CNMR (CDCl3) δ; 97.63 (
J・175.0. C-1b), 98.49 (J,
174.04), 99.24 (J, 170.4)
, 99.35 (J・170.4) , 99.49 (J
・168.9), 100.2 (J-175,5)
Elemental analysis, calculated value c+qJzoJsost・1)5C
1lCj', .

C, 73,46; H, 6,41; N, 1.
29 actual measurement value: (, 73,08; H, 6,40, N,
1.239 Rf O,63 (1/9 ethyl acetate/toluene) [α
]. + 32.63° (c O, 19, CHCl3)
'HNMR (C, D &, 60''C) δ; 1.6
0 (s, 3H, Ac), 2.97 (dd, LH
, J=3.20. 10.83. )I-2b)
, 3.39(s, 3H.

OMe), 5.38 (b, IH, J=3.05.
H-1f), 5.73(d, 18°J・1.
22), 5.8Hd, IH,J=3.36.
H-1b), 6.98-7.62 (m, 10
9H, Ar).

44→45 Compound 443 (0.93 mmoj T HF 0.
2- and methanol 0.5 d in a mixed solvent,
A small amount of 5% HC1 aqueous solution was added to make the mixture acidic, and then 3 square meters of 10% palladium on carbon was added, and the mixture was stirred overnight at room temperature under a hydrogen stream. Insoluble matter was filtered through Celite, and the solvent was distilled off under reduced pressure.

Dilute the residue with methanol 0.1 Ill! A large excess of sodium methylate (28% methanol solution) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was gel-filtered (water) using Sephadex G25.
93.6%) was obtained.

Rf O,1 (1/1/2 butanol/ethanol/
water) [α]. +2.9° (c O,0?, HzO)')
INMR (020, 60°C) δ; 4.97 (d
, IEl, J=3.66, H-1g), 5
．． 03 (d, IH, J=1.83.H-1e)
, 5.1) (br, s.

IH, H-1d), 5.19(d, Ill,
J・4.03. H-1f), 5.22(d,
It(, J=2.93.H-1b), 5.
23 (br, s, 1)1. 8-1c) 40 (α
) +41-47+48 Add 13 mg of silver perchlorate (0,063 mo + oj') to a container containing pre-dried MS4A150■,
Next, 40a 49w (
0,021 mmol) of ethylene dichloride solution 1w1
After adding 4,132 μm (0,063 smol) of ethylene dichloride solution, 0.5 μm of ethylene dichloride was added, and after stirring at the same temperature for 2.5 hours, excess triethylamine was added to make it basic, diluted with chloroform, and celite was added. Filtration was performed. After sequentially washing the filtrate with saturated NaHCO, water, and saturated NaCl water, Mg5O
It was dried and the solvent was distilled off. Pre-balatif TLC of the residue
Purified with (1/3 ethyl acetate/n-hexane), 47
27 ■ (46%) and 4815 ■ (22%) were obtained.

47 Rf O, 26 (1/3 ethyl acetate/n-hexane)'HNMR (CDCi!3) δ; 2
．． 083(s, 3H, Ac), 3.199(br,
d, IH, J=9.76), 3.234 (dd, I
H, J=3.97°10.38. H-2b), 3.3
0Hdd, IH, J・5.80.8.85), 5.3
53 (t, IH, J・2.13. H-2d),
5.380 (d, IH, J・3.66, Llb
) ” CNMR (CDC1)) δ; 98.0 (
'JC, M・172.4), 98.3('Jc, x
□172.4), 98.9 ('Jc, w□172.
4), 99.2 ('Jc, H=166.3),
99.448 Rr O, 23 (1/3 ethyl acetate/n-hexane)'HNMR (cocL) δ; 1
．． 966 (s, 3H, Ac), 2.050 (s,
38. Ac), 5.23Hbr, t, I
H, J=2.43), 5.290(d, IH,
J=1.22), 5.382(t, IH, J・
2.14), 5.543 (d, IH, J = 3.3
5) '3CNMR(CDCf2)δ; 94.5
('JC, N-167.8), 97.3 ('Jc
, N=172.4), 98.0('JC, N・17
2.4), 98.2 ('Jc, s□174.0)
, 99.4 ('Jc, m-167,8) , 100
．． 133→■ Compound 33 4.51) g (3.3 μmof) was dissolved in 0.5 d of methanol and 0.2 Ml of THF.
%HCfAfter adding a very small amount of water, 10% palladium on carbon 5■
was added and stirred overnight at room temperature under a hydrogen stream. After diluting with water and neutralizing with triethylamine)! passed. After evaporating the solvent, the residue was gel-filtered (water) using Sephadex G-10,
■ 1.6 mg (97%) was obtained.

Rf O,08 (1/1/3n-butanol/ethanol/water) IH\MR(020,60°)δ; 3.393(d
d, LH, J=3.66°10.68. H-2b)
, 3.470 (t, LH, J=9.46), 3.4
97 (dd.

IH, J: 2.75.10.07), 5.260 (d
, 1)1. J=1.83.8-IC), 5.4
85 (d, III, J=3.66, H-1b)2
9→50 Compound 29 9.16 g (8.7 mmol) was dissolved in methanol 100- and THF 30- and sodium methylate (28% methanol solution) 0.8 at room temperature.
rlLl (4 annol) was added and stirred for 5 hours. After diluting with ethyl acetate, it was washed with water and dried over HgSO4. After evaporation of the solvent, the residue was subjected to silica gel column chromatography (l/9
Purified with ethyl acetate/toluene) to give 307.28g (
87%).

Rf O, 20 (1/9 ethyl acetate/toluene) [α
]. +1). 3℃(c O,32,CHCj!,)'H
NMR(CH(1!!)δ; 1.129
(s, 9)1. t-Bu), 2.887(
n+, IH), 3.258(t, 1[(,J・
9.3I), 3.279(dd, 18.J=1
．． 83. 1). 90), 3.519 (dd,
IH, J.7.78. 9.91), 3.83
8 (t, 1B, , r・9.31), 4.378
(d.

IH, J=7.93. 1l-1b), 5.260
(d, LH, J=1.84. H-IC>, 7.
030-7.731 (m, 308.Ph) Elemental analysis Calculated value C3H6J30+oSi;C,69,61;
H, 6,57: N, 4.35 actual value: C,
69-41; H, 6,53; N, 4.29O
-X Compound 50 3001g (0.31mmoi') was dissolved in 15d of tetrahydrofuran, 60% sodium hydride 50cm (1.24m+wof) was added, and 60'C
After stirring for 20 minutes at
3 mmo i! ) and stirred overnight at the same temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was extracted with saturated NaCj! After washing with water, it was dried with Mg5O.

The solvent was distilled off and the residue was purified by silica gel column chromatography (1/8 ethyl acetate/n-hexane).
300 ■ (85%) was obtained.

51 300mg (0.26mmol) was dissolved in tetrahydrofuran 15mjl! and acetic acid 0.09ml (1
, 3 mmof) at 0°C.
-Butylammonium (IM, in THF) 1 ml
' (1 mmof) and stirred with a trowel at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated, washed with 1 aqueous saturated NaCl, and dried over MgSD4.

The container was distilled off to obtain 52155 (66%).

52 155 mg (0.17 mmoi') was dissolved in ethylene dichloride 5-: 27 μl of DAST at -23°C.
(0.2 mmo A) was added and stirred at room temperature for 1 hour. After adding water to the reaction solution and extracting with methylene chloride, the organic layer was saturated with N
aC! ! It was washed with water and dried with Mg5O. The solvent was distilled off and the residue was purified by silica gel column chromatography (1/4 ethyl acetate/n-hexane) to give 53151 (9
8%).

Add 193m of biscyclopentadienyl dichlorozirconium to a container containing 450cm of pre-dried MS4A.
g (0,66 mmof) and silver perchlorate 137 mg
(0,66 mmoi') was added, and then 53 1501) g (0,165 mmoi') was added at room temperature under an Ar flow.
) and Process 084■ (0,127 s + mojl of diethyl ether solution 10- were added and stirred for 5.5 hours. Excess triethylamine was added and filtered through Celite. The filtrate was diluted with ethyl acetate and then diluted with saturated NaHCO, water, and saturated NaCl water. After drying with washed @ MgSO4 and distilling off the solvent, the residue was purified by Prevalive TLC (1/4 ethyl acetate/n-hexane) to obtain a mixture of α and β forms 54 181 (92%).
) was obtained.

181■ of the above α-form and β-form mixture was added to 15% of acetonitrile.
m, dissolved in 1.5 m of water, added 3181 g (0.58 mmol) of ceric ammonium nitrate under water cooling, and stirred at the same temperature for 1.5 hours. After diluting the reaction solution with ethyl acetate, water and saturated NaCj ! Washed with water, washed with Mg5O, and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (1/4 ethyl acetate/n-hexane) to obtain α-isomer 55108■ (65%) and β-isomer 5654■
(33%) was obtained.

The above 56 50n (0,035a+a+oil) was dissolved in 2-methanol and 0.8 m of tetrahydrofuran, and a small amount of 5% HCffi was added, followed by 80 μm of 20% palladium hydroxide on carbon, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. After filtration through Celite, 25% ammonia water was added to the filtrate to make it basic, and the solvent was distilled off.The residue was gel-filtered using Sephadex G-25 (water) to obtain
) was obtained.

Rf 0024 (2/2/1/3 n-butanol/ethanol/28% ammonia water/water) 'EINMR (Did, 60°C) δ; 3.14
4 (dd, LH, J・8.55゜10.68.H-
2b), 3.408 (t, IH, J・9.30), 4
．． 934 (d.

IH, J=8.24. H-1b), 5.254(d
, IH, J-1,83, H-1c) 46→■ Compound 4614■ (0,007 mmoj was dissolved in tetrahydrofuran IW1 and methanol 0.5 m,
At room temperature, 7 μl of sodium methylate (5, IN methanol solution) was added and stirred for 3 hours. After neutralizing by adding Amberlyst 15 and filtering out insoluble matter, the solvent was distilled off. The residue was dissolved in 0.4 d of tetrahydrofuran and methanol Ld, and after acidifying by adding a trace amount of 5% HCl water, 2
After adding 15 cm of 0% palladium hydroxide on carbon and stirring at room temperature under a hydrogen stream for 2.5 hours, the reaction solution was filtered through Celite.
After adding 25% aqueous ammonia to the filtrate to make it basic, the solvent was distilled off. The residue was subjected to gel filtration using Sephadex G25 (water) to obtain substantially 4.8■.

Rf 0.28 (2/2/l/3 n-butanol/ethanol/28%NH,OR/water) 'HNMR (ozo, 60''C) δ; 3.302
(dd, IFI, J・3.51゜10.53.H
-2b), 3.477 (t, IH, J = 9.46),
3.498 (dd.

IFI, J・2.75.10.08), 4.230(
t, IH, J=2.44), 5.251 (d, IH
, J=2.14.8-1c), 5.258(d, LH
, J=4.88. H-1d), 5.449(d,
1)1. J・3.66, H-1b) 40 (α)→
■ Compound 40(α) 10■ (0,0043 phase O1) was dissolved in 0.4 d of tetrahydrofuran and 1III fl of methanol, and after adding a small amount of 5% H (l water), 20% palladium hydroxide on carbon was added and hydrogen was added. The mixture was stirred at room temperature under a stream of air for 2.5 hours. The mixture was filtered through Celite, and the filtrate was made basic by adding 25% aqueous ammonia, and then the solvent was distilled off. The residue was gel-filtered using Sephadex G25 (water) to obtain ■35■. Obtained quantitatively.

Rf O, 25 (2/2/ l/3 n-butanol/ethanol/28% ammonia water/water)') INMR (DzO, 60″C) δ; 3.262
(dd, 1B, J・3.36゜10.68.)I
-2b), 3.481(t, 1)1. J=9.30
), 3.503 (dd.

1)1. J・2.90.9.92), 4.062(
t, 18. J=2.90), 4.126(ddd,
1B, J=2.44.3.96.10.07),
4.252 (dd, IH, J=2.14.3.05)
, 4.973 (d, IH, J=3.66L1g), 5
．． 209(d, l) I, J・3.97. Oh-If)
, 5.327 (d, IH, J=1.83. H-1
c) , 5.417 (d, 18. J = 3.66°H
-1b) 43→■ Compound 43 101) g (0,0079 mmoj) was dissolved in 1 d of tetrahydrofuran and 2 d of methanol, and sodium methylate (5, IN methanol solution) was added at room temperature.
8 μl was added and stirred for 4 hours. Amberlyst 15 was added to neutralize the mixture, insoluble matter was filtered, and the solvent was distilled off. The residue was dissolved in 0.8 d of tetrahydrofuran, methanol 2II1) and 5% HCI! After adding a small amount of water, 30 cm of 20% palladium hydroxide on carbon was added and stirred at room temperature under a hydrogen stream for 3 hours. The mixture was filtered through Celite, and the filtrate was made basic by adding 28% aqueous ammonia, and then the solvent was distilled off. The residue was gel-filtered using Sephadex G25 (water) to quantitatively obtain 781) g of IX.

Rf O, 18 (2/2/ 1/3 n-butanol/ethanol 728% ammonia water/water) 'HIIIMR (0,0,60°C) δ; 3.363
(dd, IH, J・3.26°1). 20. H-2
b), 3.483 (t, IH, J・9.31), 3.
504 (dd.

IH, J・2.90.9.92), 4.136(dd
d, IH, J・2.29°4.12.10.07),
4.279(dd, 1)(, J・2.14.3.06
) 4.903 (d, IH, J・1.84. H-1
d) , 4.976 (d, 1) 1. J・3.66,
H-1g), 5.199(d, 1)1. J heat 4.
27.8-1f), 5.285(d, 1B, J-1
, 83, H-1c), 5.464 (d, IH, J・3
．． 66, H-1b) 48 →
was added and stirred overnight. After neutralizing by adding Amberlyst 15 and filtering out insoluble matter, the solvent was distilled off. Dilute the residue with methanol 1
I1), dissolved in 0.4 d of tetrahydrofuran and 5% H
20% palladium hydroxide carbon 15 after adding a small amount of C4 water
(2) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen stream. The reaction solution was filtered through Celite, and the filtrate was made basic by adding 28% aqueous ammonia, and then the solvent was distilled off. Sephadex G2 for the residue
5 (water) to quantitatively obtain XI5.0.

Rf O,13 (2/2/1/3 n-butanol/ethanol/28% ammonia water/water) 'HNMR (Dzo, 60°C) δ: 3.29B (
dd, LH, J・3.66°10.68. H-2b
), 3.501 (dd, IH, J=2.75.10.
08), 3.542 (t, 1) 1. J・9.31)
, 4.328 (dd, LH, J=2.14°3.0
5), 4.906 (d, l)l, J 1.5
3. If-1d), 4.989d, IH, J・3
．． 05. )I-1g) , 5.103(d, IH,J
・1.0B.

H-1e), 5.238 (d, IH, J=1.83
．． H-1c), 5.304 (d.

1)1. J=3.97. )l-1f), 5.81
0 (d, IH, J = 3.66°1l-1b).

49→XII Compound 4913 (0,004 mmof) was dissolved in 0.5 d of tetrahydrofuran and 0.5 d of methanol, 4 μm of NaO (5, IN methanol solution) was added, and the mixture was stirred at room temperature for 4.5 hours. Amberlyst 15 was added to neutralize the mixture, insoluble matter was filtered, and the solvent was distilled off. The residue was dissolved in methanol 1Id and 0.4-liter of tetrahydrofuran, made acidic by adding a small amount of 5% HCl, then 15 Inl of 20% palladium hydroxide on carbon was added, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. The reaction solution was filtered through Celite, and the filtrate was made basic by adding 28% aqueous ammonia, and then the solvent was distilled off. Gel filtrate the residue with Cefazo and Cus G25 (water)
■3.9■ (85%) was obtained.

Rf O,13 (2/2/1/3 n-butanol/ethanol/28%N1 (40H/water) HNMR (020,60'C) δ; 3.255
(br, d, IH, 1), 29°H-2b),
3.373(ddd, 1). J・2.44.6.4
1.9.46), 3.482 (t, IH, J・9.46
), 3.502 (dd, IH, J・2.75°8.
32), 3.588 (t, LH, J・9.46),
4.197(dd, 1) 1°J=1.68. 3.5
1) 4.752 (d, IH.

3.67, H-1g), 5.198(d,1)1°1.52. )I-1c) 1. 4.276 (dd, 1B, J=1.84゜J
=0.43. H-1e), 4.975 (d5.022
(d, LH, J・1.53.) IJ・3.97
．． H-1f), 5.306 (d.

5.418 (d, IH, J=3.66, H3,
35), IH, J= ld), LH, J= lb)

Claims (10)

[Claims] (1) Glycosylphosphatidylinositol anchor synthesis intermediate represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (In the formula, R independently represents hydrogen, benzyl group, methoxybenzyl group, or acetyl group) ). (2) Synthetic intermediate of the compound according to claim (1) represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is independently a benzyl group, a methoxybenzyl group, an acetyl group ). (3) Synthetic intermediate of the compound according to claim (1) represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^2, R^3 are independently a benzyl group or methoxybenzyl (R^4 represents a tert-butyldiphenylsilyl group or an allyl group). (4) Synthetic intermediate of the compound described in claim (1) represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^5 represents hydrogen or an acetyl group, R^
2 independently represents a benzyl group or a methoxybenzyl group). (5) Synthetic intermediate for glycosylphosphatidylinositol anchor analogs represented by the following formula: ▲Mathematical formulas, chemical formulas, tables, etc. are available▼ (6) Synthetic intermediate of glycosylphosphatidylinositol anchor analog represented by the following formula: ▲Mathical formula, chemical formula, table, etc. are available▼ (7) Synthetic intermediate of glycosylphosphatidylinositol anchor analog represented by the following formula: ▲Mathical formula, chemical formula, table, etc. are available▼ (8) Synthetic intermediate of glycosylphosphatidylinositol anchor analog represented by the following formula: ▲Mathical formula, chemical formula, table, etc. are available▼ (9) Synthetic intermediate for glycosylphosphatidylinositol anchor analogs represented by the following formula: ▲Mathematical formulas, chemical formulas, tables, etc. are available▼ (10) Synthesis intermediate of glycosylphosphatidylinositol anchor analogs represented by the following formula: ▲Mathical formulas, chemical formulas, tables, etc. are available▼ (10) Glycosylphosphatidylinositol anchor analogs represented by the following formula Synthetic intermediates: ▲Mathematical formulas, chemical formulas, tables, etc.▼