JPS60158128A - Preparation of (z,z,z,e,e)-hexaprenol - Google Patents

Abstract

PURPOSE:To obtain the titled compound, by subjecting (Z,Z,Z,E,E)-polyprenyl alcohol derivative obtained from (E,E)-farnesylsulfone derivative and (Z,Z,Z)- isopulenoid to desulfonation and removal OH-protecting group. CONSTITUTION:(E,E)-Farnesylsulfone derivative shown by the formula I (Ar is arryl) is reacted with a (Z,Z,Z)-isoprenoid shown by the formula II (X is halogen; R is OH-protecting group) to give a (Z,Z,Z,E,E)-polyprenyl alcohol derivative shown by the formula III. This compound is then reacted with a lithium-lower alkylamine, desulfonated, and the OH-protecting group is removed, to give a compound shown by the formula V. USE:An intermediate for synthesizing drugs, polysaccharides useful as a food, peptidoglycan, glycoprotein, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to (z, z, z, g, g)-hegisaprenol, which is one of the polyprenols having a sterically specific structure, namely benzprenol-6 (Betulapr).
The present invention relates to a method for producing enOl).

In recent years, various polyprenols have been isolated from animals, plants, and microorganisms, and subsequently these polyprenols have been converted into polysaccharides,
It is gradually becoming clear that it plays an important role in living organisms as an intermediate in the synthesis of peptidoglycan, glycoproteins, etc., and it has great potential to be used in foods, medicines, foods, etc.

However, since these polyprenols are composed of isoprene units, there are cis-type isoprene units and trans-type isoprene units, and the natural type has a specific arrangement, so it is difficult to synthesize it. It has traditionally been difficult to obtain this substance, and the only way to obtain it is to extract and isolate it from animals and plants.

However, the method of extracting and isolating it from nature has limited resources, is not suitable for mass production, and is not industrially viable.

Benzprenol-6 of the present invention also has the following structural formula, but has two trans isoprene units and three cis isoprene units at the alcohol terminal.

For this reason, it has hitherto been considered difficult to synthetically produce such polyprenols.

Therefore, the present inventors have completed the present invention as a result of extensive research over many years in order to synthetically obtain a compound having the same steric configuration as naturally occurring benzuprenol-6.

That is, the present invention is illustrated as follows.

02Ar (In the formula, R means a hydroxyl group protecting group, Ar means an aryl group) In the polyprenylaryl sulfone compound of (II), which is the starting material, 3 adjacent to the alcohol terminal
Each of the isoprene units is a cis isoprene unit, and the two adjacent isoprene units are trans isoprene units (Z, Z, Z, E, F type).

In formula (It), the aryl group includes, for example, a phenyl group, a para-tolyl group, a xylyl group, a naphthyl group, and a para-tolyl group and a phenyl group are preferred.

R means a hydroxyl protecting group, and typical examples include lower alkyl groups such as methyl, ethyl, propyl, and butyl, aralkyl groups such as benzyl, phenethyl, and benzhydryl, 7-cetyl, propionyl, butyroyl,
Acyl groups such as pivaloyl, tetrahydropyranyl groups,
These include methoxymethyl group and methoxyethoxymethyl group.

This step is a step of desulfonating the polyprenylaryl sulfone compound (■) and removing the protective group for the hydroxyl group, and is usually carried out in the presence of lithium-lower alkylamine. The most preferred lower alkylamine is ethylamine. The reaction solvent is lithium-
Since the lower alkylamine is prepared using the lower alkylamine itself as a solvent, it does not need to be used in particular, but an ether solvent such as ethyl ether or tetrahydrofuran may be used in combination. The reaction temperature is -50°C or less, preferably -60 to -80°C.

The polyprenylaryl sulfone compound (II) used as a starting material in the present invention is, for example, (in the formula, X means a halogen, R means a hydroxyl group protecting group) ↓ (fl) That is, the imprene unit is a trans form. It can be obtained by reacting the sulfone compound (III) with a compound (IV) in which all three imprene units are in the cis form. This reaction can be carried out, for example, by reacting tetrahydrofuran and hexamethylphosphorylamide in a mixed solvent in the presence of n-butyllithium.

Furthermore, the compound (+10,
That is, (m,]]X)-farnesylarylsulfone can be easily produced as (E,E)-7-arnesol.

On the other hand, the compound Cy>s is another starting material.

That is, (z, z, z) -o,, the compound of the present invention is (Z.

Z , Z , ]lLl, E) - It is an extremely important compound when producing hexaprenol, for example as follows (in the formula, R represents a hydroxyl group protecting group and Ph represents a phenyl group) ↓ That is, tetrahydropyranyloxyacetone (V)
In addition, the hydroxyl group is protected with, for example, a benzyl group (z, z
) -(4,a-dimethyl-4,8-decadiene-1-
I) A triphenylphosphonium iodide compound (b) is reacted, for example, in the presence of n-butyllithium to form a compound (4), and this tetrahydropyranyloxy group is further eliminated to form a compound represented by -. (
2,2.2)-2,6,10-dodecatrien-1-ol derivative, which is then halogenated to give a cis isopredo compound (6)).

The (z, z) -(4,8-dimethyl-4,8-decadien-1-yl)tris-7-difluorosphonium iodide compound (b) used in this removal can be produced, for example, by the following method. be done.

(In the formula, R means a hydroxyl group-protecting group) (In the formula, To means a tosyl group, and R means a hydroxyl group) is used as a starting material, the hydroxyl group is protected with, for example, a benzyl group, and
compound (3), and N-bromsuccinimide (
NBS) to form an epoxy compound (4), then treatment with periodic acid, Na:Em, etc. to cleave the epoxy group to form an alcohol (b), which is then reacted with tosyl chloride. A compound (m) is obtained, and this compound is further treated with Na to give iodide (cave), which is then treated with triphenylphosphine to form a triphenylphosphonium salt (ro).

Next, examples of the present invention will be shown, but it goes without saying that the present invention is not limited only to these examples.

Example (Li (2Z, 6Z, 1 0Z, 1 4B, 1 8] 1
ii) Dissolve -5゜(u+,E)-farnesyl p-tolylsulfone 327'/(0,909 mmol) in a mixed solvent of anhydrous tetrahydro7rane (THF) 4 d and hexamethylene phosphorylamide (HMPA) 1 at. and cool to -70°C. n-Butyllithium (1.s M in hexane) 0.6 ml (0.9 mm
1) was added and stirred for 20 minutes. This is K (Z, Z, Z)
-12-chloro-3,7,11-trimethyl-2゜6
．． 10-)'Decatrienylbenzyl ether 210'
THF (5tttl) of JF (0,606mml)
The solution was added over 5 minutes and further stirred at -70 to -55°C for 2 hours. After adding 2 d of methanol, the mixture was heated to room temperature and poured into water 101. Then ether-hexane (1
:1) Extraction, washing (saturated saline), drying (wso,)
After that, it was concentrated under reduced pressure to obtain 943 crude products. This was subjected to silica gel (100?) column chromatography to obtain a 40% PF! /hexane to obtain 364 title compounds (yield 90%) having the following structural formula.

S 02A r (in the formula, ph represents a phenyl group, and Ar represents a p-)lyl group) on: : 1.5! s 95 0 engineering R(neat)il: 1660, 1300, 11
45,740,7000 NMR(ODQt,)δ:
1.19 (d, J-1,5H2,5H)+1,
59 (8,9H) t 1.65 (s, 6H
) *1.74 (s, 5H), 2.00 (m, 16H
).

2.45 (s, 3H), 2.45-2.90 (m.

2H), 5.85 (sex'tet, J-=,,
and4Hz.

IH), 4.00 (d2.T=6Hz, 2H), 4
．． 49 (8, 2HL 4.95 (d, J=10Hz
, IH).

5,08 (be, 4H) y 5.41 (t,
:I-6Yu, IH).

7.32 (s, 5H), 7.30and7.72
(ABq.

J=8 Hz, 4 H) 298 m51 (43 atm) of lithium is dissolved in 20 g of anhydrous ethylamine to give a deep-colored solution. -7
(2Z, 6Z, 10
z, 14B, 18E) -5, 7.

11.15,19.23-hexamethyl-13-(p-
tolylsulfonyl)-2,6,10,14°18.22
- Tetracoza hexaenyl benzyl ether 970 (
1,45 mmol) in ether (1 sm/) solution at 30
The mixture was added over a period of 1 minute, and the mixture was further stirred at the same temperature for 1.2 hours. While keeping the temperature as low as possible, add isoprene and methanol one after another and raise the temperature to room temperature. Add saturated aqueous ammonium chloride solution and carefully concentrate under reduced pressure. The residue was extracted with ether, washed (water and saturated saline), and dried (Na2
5o, ) and then concentrated to obtain crude product 641'/. This was subjected to silica gel (35 ml) column chromatography and developed with 1096 ethyl acetate/hexane to obtain 542 venlaprenol-6 having the following structural formula (yield: 8
8%).

On also 5: 1.50 0 8 0 engineering R (neat) cIrv": 3500, 16
60, 1445.

1375.1000.830 0 NMR (0Dat,) δ: 1.60 (s, 9
H), 1.69 (e, 9H).

1.75 (sjH), 2.07 (m, 20H), -4
,09((1,2H), 5.11(bθ,5H).

s, 4s (t, 1H) Applicant's agent Kaoru Furuya Procedure amendment! , (Method) % formula % 2. Name of the invention (Z, Z, Z, E, B) - Process for producing hexaprenol 3. Relationship with the person making the amendment case Patent applicant (021) Eisai Co., Ltd. 4. Agent Person Chugai Hill 1-3 Nihonbashi Yokoyama-cho, Chuo-ku, Tokyo 1984 4
Month 24th (shipping date) 6. Specifications subject to amendment 7. Contents of amendment

Claims (1)

[Claims] 1. Lithium is added to the (Z, Z, Z, El, B)-polyprenyl alcohol conductor represented by the general formula (in the formula, R represents a hydroxyl group protecting group and Ar represents an aryl group). - A method for producing (Z, Z, Z, B, Et)-hexaprenol represented by the following structural formula, characterized by carrying out a desulfonation operation with a lower alkylamine and removing a hydroxyl protecting group. . (g, m)-7 Arnesyl sulfone represented by the general formula C (wherein, Ar means an aryl group), and the general formula (wherein, (Z, Z, Z)-isoprenoid represented by
z, z, z, F+, E)-polyprenyl alcohol derivative is obtained, and then the compound is subjected to a desulfonation operation with lithium-lower alkylamine, and the protecting group of the hydroxyl group is removed. A method for producing (Z, Z, Z, Fi, E)-hexaprenol represented by the structural formula.