JPH01228938A - Asymmetric synthesis of diterpene - Google Patents

Abstract

PURPOSE:To obtain a diterpene useful as pharmaceutical or its raw material, in high yield by using a novel optically active cyclohexane derivative as a raw material and stereo-selectively cyclizing the compound in the presence of an acid catalyst to effect asymmetric synthesis of the subject compound. CONSTITUTION:The objective compound of formula II [the 6-CH3 and the 4- alkoxycarbonyl, etc., on the cyclohexane ring have steric configuration directing in the same direction as the cyclohexane ring and the 4-CH3 and 5-H have steric configuration of the same direction different from the above direction] is produced by the stereo-selective cyclization of the novel optically active cyclohexane derivative of formula I [R' is H, (alkoxy-substituted) alkyl or (protected) OH; R'' is H or alkyl; n is 1 or 2; the 1-phenylalkyl and the 2- alkoxycarbonyl, etc., on the cyclohexane ring have steric configuration directing in the same direction as the cyclohexane ring] in the presence of an acid catalyst to effect asymmetric synthesis reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for asymmetric synthesis of diterpene derivatives. The diterpene derivatives obtained according to the present invention are useful as medicines or raw materials thereof.

<Prior art> The cyclic diterpene bodocarpic acid
cacid) and biciferic acid (pisiferic acid).
acid) and the like have antitumor activity and are useful as medicines or raw materials thereof. For example, podocarpic acid has antitumor activity, such as nagilactone.
) and atisine type diterpene alkaloids.

Conventionally, methods for synthesizing optically active diterpenes have not been well known, and even if known, the yield was low.

<Problems to be solved by the invention and means for solving the problems> The present invention aims to provide an efficient method for synthesizing optically active diterpenes.

According to Honsha 5inc, l-phenylalkyl-methyl-coalkoxy (or hydroxy) carbonyl-6
By ring-closing an optically active form of -methylene-cyclohexane with an acid catalyst, the A and B rings of a tricyclic diterpene can be stereoselectively synthesized in good yield.

To explain the present invention in more detail, the cyclohexane derivative that is the raw material of the present invention is a new substance, and can be synthesized from optically active nitroolefin lactone in the following manner.

mass, nitroolefin lactone (I), Miche
Al addition adds an alkoxy group to the phenyl ring, usually 0
A phenylmethyl (or ethyl) group which may have a 1 to C5 alkoxy group is introduced.

(I) (n) [In the formula, m represents O or /, R' represents an alkoxy group or hydrogen] That is, [Kaoru Fuji, Ki Node et al.: J, A, C.

S,-mu01. P3g! ! , /9g&and5ynthe
sis/9g? , AA', P7! ? ] Mich
By eal addition, the diastereomer of (II) can be obtained according to the above formula. In this reaction, it is also possible to add a catalytic amount of Cul to the Grignard reagent (yield 0%).
, IJ Nier reagent alone is preferred.

In compound (II), when m = /, abietane such as podocarbic acid, dehydroabietic acid, etc.
j In the podocarpane skeleton compound, m=0
In the case of 0, it can be induced into a compound having a gibberellane skeleton.

After opening the lactone ring of compound (n), it is reacted with methanesulfonyl chloride to methanesulfonylate it, and then reacted with sodium iodide to form a nitroalkane iodo compound.

This iodine introduction reaction can be carried out in high yield according to conventional methods.

R′ (n) (m) Compound (
[r) is treated with sodium hydride (NaH) to undergo intramolecular cyclization to give a nitrocyclohexane derivative GV).

Although it is possible to intramolecularly cyclize the methanesulfonylated form as it is before converting it into the nitroalkane iodo form (VI), it is preferable to carry out intramolecular cyclization as the iodo form.

(III) C■) Compound GV
) is substituted with an oxygen atom by a Nef reaction to obtain a cyclohexanone derivative (V). The reaction is a compound (V
After reacting with approximately equivalent amount of titanium trichloride (1), it may be reacted with an excess amount, for example, 6 equivalents of titanium trichloride.

(rV) (V) Among the diastereomers of compound (V), the trans form can be converted into the cis form by an isomerization reaction with an acid.

The carbonyl group of the cis form of compound (V) was converted to the Nozaki modified method Wit
Convert to methylene group by tig reaction (V)
From the (Ml)S-configured nitroolefin lactone (I-8), the S-type compound (VI-8) is
A compound of type R (Vl-FL) can be obtained from a nitroolefin lactone of configuration (1-R).

(Vl-8) (VT-R) Through the above steps, an optically active cyclohexane derivative, which is a raw material of the present invention, is obtained. In the above process, R' is preferably hydrogen, an alkyl group, or an alkoxy group. The number of carbon atoms in these alkyl groups is arbitrary, but is usually C1 to C5. R' may also be an alkoxyalkyl group such as methoxymethyl.

The compound (Vl) obtained above can be used as a raw material of the present invention after converting the alkoxy group of the benzene ring into a hydroxyl group, if desired. Furthermore, the hydroxyl group may be converted into an acyloxy group by esterification and then used as a raw material for the present invention.

The ring-closing reaction may be carried out by dissolving compound (Vl) in a solvent and treating it in the presence of an acid catalyst. The simplest is the compound (Vl)
When dissolved in methanesulfonic acid, added with phosphorus pentoxide (P2O5), and treated at θ℃ to room temperature, the compound (■) stereoselectively formed due to the participation of adjacent groups of the alkoxycarbonyl group.
It is possible to obtain an optically active form of.

In addition, as an alternative method, compound (Vl) is dissolved in methylene chloride or benzene, and A I C13,5nC14, BF3
, ZnCl2, TiCl4, etc. may be added and the treatment may be carried out at room temperature to reflux temperature.

(■-A) The compound with n = 2 and R' at the 73rd position is 0-alkylbodocarbic acid methyl ester, and podocarbic acid is obtained by dealkylating this by a conventional method. Bodocarpic acid has already been used as taxodione and nagi.
lactone C, callitric acid
, hinokinomethylester ,
trachiloban −/9- oil a
cid has been synthesized, and optically active podocarpic acid is an important compound as a synthetic intermediate.

According to the method of the present invention, basic skeletons A/B of cyclic diterpenes
) The lance ring can be synthesized stereoselectively.

Furthermore, dealkylation of a compound (■-B) with R' at the 73rd position with n=2 yields an optical isomer of bodocarpic acid, that is, (-)-bodocarpinic acid, which has already been reported by Mori et al. (Tetrahedron, 2 II, 309
! ; (/ 9 A g ) :] Kaureno
ic acid.

Furthermore, 5teviol [: 1. F. Cooke
tal, Tetrahedron crawl, 74. ,?
(/97A)).

Also, by Mori, Valenta et al.
Ta.

et at, Tetrahedron 1etter
KoQ37 (/9A11): Ni, Mori etal
,Agr,Biol,Chem,,3s 9sb(/
? 7 / )] Veatchine p Gar
Diterpene alkaloids such as rgine have been synthesized.

Furthermore, when the trans isomer of compound (V) is used as a raw material, derepipodocarbic acid can be synthesized through a similar synthetic route. The synthesis of dehydroabietic acid from this is carried out by known methods (J. W. Hoffman.

J, Org, Chem, as, 3/sa(/qriO
)] is possible.

The present invention will be explained in more detail below with reference to Examples.

H:β-H (n-b) H:α-H Under nitrogen atmosphere, add 70M Grignard reagent (without stirring)
J, g mmole, ether solution) was added to 20 g of tetrahydrofuran. After cooling to -7g°C, the nitroolefin lactone compound (2,Q,?mmole ppurity t7%) represented by the formula (I) of ttttqm9: K, Fujii, M, Node et
al., J.A.

C, S, , Mu01. ．． 3g! ! ;, /9g&)20
ml of tetrahydrofuran solution was gradually added, and stirring was continued for an additional 2 hours. A saturated ammonium chloride solution of JOxl was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes.

Subsequently, approximately 7θat of o,tN hydrochloric acid is added, and eo
Extraction was performed with o-methylene chloride. The solvent was distilled off under reduced pressure, and the resulting concentrate was subjected to column chromatography (hexane and hexane-methylene chloride systems, 2:/
and/:co), sq6■ compound (II-a)
and (II-b) were obtained (3.3:co, yield 76.
5%).

Subsequently, the product was developed by thin layer chromatography (diethyl ether-hexane system, A:/) to obtain 36 µm (na) and 220 µm (II-b).

Further, the compound (II-a) was recrystallized from diethyl ether and chemically analyzed, and it was found to have the following physical properties.

II Point C℃) 2 7-5'-7-Misaki MS analysis: M+32/, / &? ? Bimolecular formula C1? H,
N0s (Theoretical value 32/, /!; Ir22) IR ((y-Re: /7/3./601:, /!; 1
,0. /30za.

/ KoSO'H-NMRδ (ppm): /, J J (j
H,S LDCI3 J, 7q (jH, s), II, 30 (koH, m).

Il,! 2. ! , 9.7 (2H, ABM typ.
AB part of e, Jl=j)lz, J2=/J)lz C
6. The 3. ri, 0 9 (QH, AB t
ype, J "za Hz) Synthesis Example U Synthesis Example/Compound (I[-a), 773mt
y (/, / A mmole) under nitrogen atmosphere,
/M sodium methoxide solution at 0°C dissolved in dehydrated and dried methanol 301! After adding r and grnl, the mixture was stirred at room temperature for 6 hours. Add 4Z to this reaction solution at 0°C.
After gradually adding ff Otll acetic acid, the solvent was distilled off under reduced pressure, and the residue had a concentration of 0. j N @20m of acid
1 and extracted with 3 oad of methylene chloride. After evaporation of the solvent, the obtained 'IS/~ residue was dissolved in dehydrated and dried methylene chloride romt, and 99 μl of methanesulfonyl chloride and 17 g μl of triethylamine were gradually added at 0°C, followed by continuous stirring for 30 minutes. did.

After adding 100 ml of methylene chloride to the reaction solution and performing the same operation as in Synthesis Example, 641! ; m9
Dissolve the residue in 30 ml of acetone and add sodium iodide/, 7 ts,! ? (/ /, Ammole)
was added and stirred at room temperature for 10 hours. 100 ml of methylene chloride was added to the residue after the solvent was distilled off, and after washing, the same operation as above was performed, and the resulting residue was eluted with column chromatography (hexane-methylene chloride system, 3:l). The compound (IJJ) of tlbgm9 was obtained (yield g
7%).

MS analysis; dab3.0gg72. Molecular formula C18826
NO51 (Theoretical value Ql, 3.Og!; gco) IR (crn-') 2 /')/! ;, /
3;40. /! ;Og, 7211g'H-
NMRδ (ppm) ”,” (3H+S LD
C13, 7J7 (JH, t, J=7Hz), 3.1-. 1(J
H,s),,3.7g(,3H,s),'1. ．． 2g.

Da, b, 2 (2H, AB part of ABM type.

J1=jHz, J2=/, 7H2), A9g2゜7
．． 06 (QH, AB type, J = g Hz)
Synthesis Example 3 Under nitrogen atmosphere, hydrogenation of 99μ) IJium (60
% oil, 2. tt? 3; mmole) was added to 30 ml of dimethylformamide, and the compound (III) obtained in Synthesis Example 2 was added to 30 ml of dimethylformamide, and the /! After adding rut dimethylformamide solution and stirring for 79 hours, the mixture was stirred at room temperature for 6 hours. After the reaction was completed, acetic acid was gradually added at 0° C./gOμ, and after stirring at room temperature for 30 minutes, dimethylformamide was distilled off.

To the residue/! After adding fOml of methylene chloride and performing extraction, the reaction mixture was eluted with column chromatography (hexane-methylene chloride system, 3:l), /Q
4 m9 of compound <■) was obtained (yield (73,!;%)
.

MS analysis: 33! ;, /7AOg, molecular formula C,,82
5No.

(Theoretical value 33!;, 1732g) IR (CrrL-'): /7/2.110g, /!
;! ;0. /! ;Og.

/2! ;0'H-NMRδ (ppm) "1.2" (3H
+s) +DCI3 3.6! ; (3H,s), 3.77 (3H,s
).

! , / J(/H, dt, J1=5Hz, J2=1
0Hz), A, 7q, ? , (1) J(4'H, AB
type, J = Hz) Synthesis example q (IV) (V-a) Synthesis example 3
Compound (rV) / 33 m9 (0, If
03 mmole) was dissolved in methanol under a nitrogen atmosphere, booμl of 7M sodium methoxide solution was added, and the mixture was stirred at room temperature for 7 hours (solution A).

On the other hand, ammonium acetate? 4IOm9 (9.6mm
ole) in 2.3 ml of water, 20% titanium trichloride solution/,! under nitrogen atmosphere. , 2 ml (/,
76 mmole) and stirred at room temperature for 70 minutes.

Next, the above solution A was gradually added dropwise to this solution at 0°C,
Stirring was continued for 3 hours at room temperature.

Next, 30 ml of methylene chloride was added, and 2 ml of 0.5N hydrochloric acid was added.
Methylene chloride under acidic conditions with 0ml added/! ;Oml
The solvent was distilled off to obtain /co/~ compound (V-
a) was obtained (yield 99%).

MS analysis: 30 Da, / 6 Da / 79 molecules 2〇,, H2,0
゜ (Theoretical value 30 da, /A?, ??) IR (crrL-'): /7/s, /bog, /
sog, /xs.

H-NMRδ (ppm): /, 02 (3H
,s).

DCI3 Jj4<(JH,s), 3.7g(3H,s).

Alg / , 7.07 (9H, AB tYI)
e, J=gHz) Synthesis example (V-b) (V-a) Synthesis example/
Compound (v-b) was obtained from compound (n-b) obtained in the same manner as in Synthesis Examples. This (v-b) compound 4<, 21q was dissolved in methanol krrIl,
After adding 10rLL9 of toluenesulfonic acid, the mixture was stirred at room temperature for 29 hours. After distilling off the methanol and extracting with methylene chloride, 'l/,! m9 compounds (V-a) and (V-b) (ratio/2/) were obtained. Subsequently, this mixture was separated by thin layer chromatography (hexane-diethyl ether system, /:/).

Synthesis Example 6 Compounds (V-a) of 47~ were dissolved in methylene chloride, and 3 ml of Nozaki modified Wittig reagent (methylene bromide-zinc-titanium chloride solution) was added at room temperature. After the addition, the mixture was stirred at room temperature for 30 minutes.

Subsequently, 201 ml of methylene chloride was added, 20 ml of 0.3 N hydrochloric acid was added, and extraction was performed with 30 ml of methylene chloride. After distilling off the solvent, we obtained! ;1Ir
The reaction mixture of n9 was eluted with column chromatography (hexane-methylene chloride system), and compound 33 (Vl
-s) was obtained (yield 7s%).

'HNMRaCDC13 (ppm): /, /7
(3H,S).

3, b3(3H,S), 3.7&(3H,S).

4', 72(/H,br,)t'1. t g (/H
9br,)+/,,79. 7. OQ (Hiro H, AB t
ype, J = gHz) Example/Methanesulfonic acid of 6 gOμj /θO under nitrogen atmosphere
After adding it to the phosphorus pentoxide in (1), it was stirred at room temperature and added to the compound (■-s) 3 / In9 obtained in Synthesis Example 6 at 0°C.

Subsequently, the mixture was stirred at room temperature for 1S minutes, and then extracted with kOrnl methylene chloride. After distilling off the solvent, the obtained 3
The reaction mixture of step 5 was eluted with column chromatography (hexane-methylene chloride system, 3:/) to obtain 2grlL9 of the compound represented by formula (VII) (yield 90%)
. When recrystallized with methanol, the physical properties were as shown below.

Melting point: /29~/30. ! r℃ (commercial product, /2
9~/J0.3;'C) MS analysis: 30λ/g69Co9 Molecular formula C19H2603
(Theoretical value 30λ/gza/ko) [α): +/, 2g @ (commercial product /, 700)
IR (cm-1): /qO! , 1b00. /! rbO
,/! ;! 0°/230'H-NMRδCDCl5(pp: /,03
<3H,s).

/, 2 (JH, s), 3.46 (3H, s).

, 7.77 (3H,S), b, l, 0-7,0/(J
H.

ABCtype) The physical properties of the synthetic product obtained in the present invention and the commercially available product were the same.

(Effects of the Invention) According to the method of the present invention, diterpene compounds useful as pharmaceuticals can be produced in good yield by a novel synthesis method.

Procedural Controversy (Method) l Indication of the Case Patent Application No. 55355 of 1988 2 Title of Invention Asymmetric Synthesis of Diterpenes 3 Person Making Amendment (596) Mitsubishi Kasei Co., Ltd. Mitsubishi Kasei Co., Ltd. 1°L , (28°ゝ °°“°
17-1. 'Yumiwo (6806) Patent attorney Hasegawa - Makoto 1. J.

(1 other person) 5. Date of amendment order May 31, 1988 (dispatch mortar)
6 Subject of amendment Specification

Claims (2)

[Claims] (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [VI] [In the formula, R' represents hydrogen, an alkyl group that may be substituted with an alkoxy group, or a hydroxyl group that may be protected, and R'' represents hydrogen or an alkyl group, and n is 1 or 2. The phenylalkyl group at the 1-position and the alkoxy (or hydroxy) carbonyl group at the 2-position of the cyclohexane ring have a steric configuration in the same direction with respect to the cyclohexane ring. , and the hydrogen at the 1st position and the methyl group at the 2nd position have the same steric configuration, which is different from these.]Stereoselectively ring-closing an optically active cyclohexane derivative represented by Features ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼・・・・・・・・・
[VII] [In the formula, R', R'', and n have the same meanings as in the formula [VI]. The methyl group at the 6-position of the cyclohexane ring and the alkoxy (or hydroxy) carbonyl group at the 4-position are relative to the cyclohexane ring. The methyl group at position 4 and the hydrogen at position 5 have a configuration in the same direction, and the methyl group at position 4 and the hydrogen at position 5 have a configuration in the same direction. (2) A claim characterized in that the ring-closing reaction is carried out in the presence of phosphorus pentoxide (P_2O_5) and an alkylsulfonic acid (
1) The asymmetric synthesis method described.