JPH03106887A - Optically active alcohols and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound having a silyl group at the gamma-position, expressed by formulae I or II [R<1> to R<3> represent 1-10C (substituted)alkyl or (substituted) phenyl; R<4> represents 1-10C (substituted)alkyl or (substituted)phenyl; X represents H or OH-protecting group]. EXAMPLE:A compound expressed by formula III. USE:An intermediate for synthesis of various physiologically active substances such as prostaglandins. PREPARATION:An optically active alcohol expressed by formulae IV or V, as necessary, is protected and oxidized preferably by a method such as the Swern oxidation or Collins oxidation.

Description

[Detailed Description of the Invention] The present invention is useful as a physiologically active substance in itself, and
contains a secondary allyl alcohol skeleton in its molecular structure, and
Optically active alcohols having a silyl group at the γ-position useful as intermediates for the synthesis of various synthetic active substances such as prostaglandins having two consecutive asymmetric centers in the molecule, protected forms thereof, and methods for their production. ．． The section that Nobi is trying to explain is that secondary allyl alcohol is itself a useful compound.
It has also been widely recognized as a useful synthetic intermediate. In particular, in recent years, various physiologically active compounds containing a secondary allyl alcohol skeleton in their molecular structure have become widely known, but many of these compounds are optically active forms, and optically active forms of secondary allyl alcohol. This has become an important issue from an industrial perspective. In particular, when considering the synthesis of the final target compound (many of which contain an optically active allyl alcohol skeleton in their molecular structure, resulting in more complex compounds and their stereoisomers), these compounds are advantageous. Allyl alcohol has optical activity and is desired as an intermediate that can be used in a variety of reactions. As such an optically active allyl alcohol, for example, the following general formula (1゜P)/R2OH having a halogen atom at the γ position (where R is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted alkyl group) is used. It is an unsubstituted phenyl group.
) is known as a very important synthesis intermediate for the synthesis of prostaglandin compounds, which are new types of pharmaceuticals (Patent Application No.
No. 38169). Furthermore, in recent years, as shown in the reaction formula below, which is a type of prostaglandin, 2I and allyl alcohol having tin at the γ position are synthesized in 9 steps from epoxy alcohol obtained by the asymmetric Sharpless reaction of nerol. (N, Kolb et al., Tstrahedron
．． Lstt. , 29. 8 7 e 9 , (
1988)) is known. Mexiprostil (Mexiprostil)
) is desired as a secondary allyl alcohol having two consecutive asymmetric centers in the molecule as a useful intermediate for synthesis such as the ω chain of Conventionally, the synthesis method for the ω chain of mexiprostil was 20S1, but the selectivity of the asymmetric Sharpless reaction was low in the above synthesis method, and the optical purity of the intermediate was insufficient to be used as a pharmaceutical intermediate. However, there was a problem in that complicated purification was required after synthesis. The present invention was made in view of the above circumstances. It has high optical purity and is useful as a physiologically active substance in itself. It is also useful for various physiologically active substances such as prostaglandins, which contain a secondary allyl alcohol with two consecutive asymmetric centers in the molecule as a backbone. The purpose of this invention is to provide optically active alcohols having a silyl group at the γ-position that are useful as synthetic intermediates, and a method for producing the same. In order to achieve the above object, the present inventor has made extensive studies and found that the following general formula, which was previously proposed by the present applicant in Japanese Patent Application No. 63-57017, can be obtained by carrying out a press reaction. The optically active epoxy alcohols represented by the following general formula (V) and the following general formula (VI) (wherein Rt, R@, and R3 are the same as above) have extremely high optical purity; The epoxy alcohol is prepared using the following reaction formula (where R'', R'', and R'' are each a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, even if they are the same as each other). An optically active alcohol of the general formula (Iffl, (fV) is obtained by deriving the diallyl alcohol represented by the asymmetric formula OH 0x (I[I) as follows. By monomerizing this optically active alcohol of formula (m) or (mV), the following general formula (1
) or the following general formula (n) Ox OX (where R4 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, and X is a hydrogen atom or a hydroxyl group protecting group. ) A novel optically active ketoalcohol having a silyl group at the γ-position and its protected form can be synthesized with high optical purity,
Moreover, these optically active keto alcohols and their protected forms are not only useful as physiologically active substances in themselves, but also prostaglandins whose molecular structure contains a 2R allyl alcohol having two consecutive asymmetric centers in the molecule. The present inventors have discovered that this compound is useful as a synthetic intermediate for various physiologically active substances such as, etc., and have accomplished the present invention. Therefore, the present invention provides an optically active alcohol having a silyl group at the γ-position represented by the above general formula ([1 or (n)), and an optically active alcohol represented by the above formula (m) or (mV). Provided is a method for producing optically active alcohols represented by the above formula (1) or CIll formula, characterized in that the present invention is further described in detail below. 0
A substituted or unsubstituted alkyl group or a substituted or unsubstituted phenyl group, specifically methyl, ethyl, n
-provil, i-provil, n-butyl, i-butyl,
t-butyl, amyl, hexyl, hebutyl, octyl,
Examples include groups such as nonyl, decyl, phenyl, p-tolyl, m-chlorophenyl, and p-methoxyphenyl.6 Note that R1, R2, and R3 may be the same or different from each other.

Furthermore, as mentioned above, R4 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, and specifically, R4 represents methyl, ethyl, n
-propyl, i-propyl, n-butyl, i-butyl,
t-butyl, amyl, hexyl, heptyl, octyl,
nonyl, decyl, 2-methylhexyl, 2-methyl-2
-hexyl, 2-hexyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hexyl-4-yl-2
-yl, hebut-4-yn-2-yl, 2,6-dimethyl-hebut-5-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, hexer-1-yl
En-2-yl, 3-ethoxy-2-methyl-propan-2-yl, ethoxyethyl, 5-methoxyhexyl,
6-methoxy-2-hexyl, methyl halide, n-butyl halide, n-pentyl halide, nonyl halide, phenyl, benzyl, phenyl halide,
n-pentyloxymethyl, 1-ethoxy-2-methyl-propan-2-yl, phenoxymethyl, pendyloxymethyl, p-chlorophenoxymethyl, 2-phenylethyl, pendyloxyethyl, p-fluorophenoxy Methyl, phenylacetylenyl, m-chlorophenoxymethyl. Mention groups such as m-trifluoromethyl-phenoxymethyl, l-butyl-cycloprobyl, 3-ethyl-cyclopentyl, penzothiophen-5-yl, 2-octenyl, 3-methoxycarbonylprobyl, vinyl, etc. Can be done. Further, X is a hydrogen atom or a hydroxyl group protecting group, and examples of the hydroxyl group protecting group include a trialkylsilyl group (e.g. trimethylsilyl group, t-butyldimethylsilyl group, phenyldimethylsilyl group),
Alkoxyalkyl groups (e.g. methoxymethyl group, ethoxyethyl group, 2-tetrahydropyranyl group), aralkyloxyalkyl groups (e.g. penzyloxymethyl group),
Trityl groups and further acyl groups (eg, acetyl groups, p-nitrobenzoyl groups) can be mentioned. The optically active alcohol of formula (13 or ([3) and its protected form can be obtained by oxidizing the optically active alcohol represented by the following general formula (m) or the following general formula (IV) 0X, respectively. In this case, the oxidation is preferably performed by an oxidation method in which the compound of the formula (I[[], (rV)) is protected as necessary and this protecting group is not removed.
) oxidation, Collins oxidation, etc. are preferably employed. Note that there are no restrictions on the oxidation conditions, and normal conditions can be used. Furthermore, after the oxidation is complete, it is desirable to deprotect by a conventional method, if necessary. The optically active alcohols of formulas (III) and (IV) can be expressed by the following general formula (Vl 0H or The following general formula (Vll (wherein, Ri, R'', R''li)
6. ) to obtain an optically active epoxy alcohol,
These optically active epoxy alcohols are each expressed by the following reaction formula (in the formula, R"R" and R' each have a carbon number of 1 to 10
are substituted or unsubstituted alkyl groups or substituted or unsubstituted phenyl groups, which may be the same or different from each other. Same below. ) can be induced and combined into the asymmetric form 0H 0X [11] OX (where R4 is the same as above). When deriving (Iff) or (IV) from the above (V) or [VI), first the hydroxyl group of (V) or (Vl) is protected with a hydroxyl-protecting group X by a conventional method. X is a trialkylsilyl group (e.g. trimethylsilyl group, t-butyldimethylsilyl group), an alkoxyalkyl group (e.g. methoxymethyl group, ethoxyethyl group), an aralkyloxyalkyl group (e.g. penzyloxymethyl group), a trityl group, Further examples include a tetrahydropyranyl (THP) group, but an alkoxyalkyl group such as an ethoxyethyl group is preferred because it can easily withstand the following desilylation conditions. Next, the silyl group at the base of the epoxy part is desilylated using a conventional method. Usually 0.1 fluorine-based compounds such as tetra-n-butylammonium chloride or hydrogen fluoride
~4 equivalents and dimethyl sulfoxide (D
MSO). React using tetrahydrofuran (THF) or the like. These may contain some moisture or may be used in combination. Furthermore, the desilylated epoxy compound is treated with a reducing agent such as lithium aluminum hydride, or an organometallic reagent such as dimethylmagnesium, methyllithium, methylmagnesium chloride (Grignard reagent), dimethylcopperlithium, etc., to induce cleavage of the epoxy. An alcohol compound (I [I] or (IV) is obtained. This reaction may also be carried out under the reaction conditions of conventional epoxy cleavage. However, in the case of the compound of the present invention, since the substrate contains an olefin moiety, a large excess of the reducing agent is used. It is preferable to carry out the process under as mild conditions as possible, as extreme conditions such as using or strongly heating increase the side reaction that saturates the olefin moiety.Usually, reducing agents or organometallic reagents are added to the desilylated compound. 0.8~
It is sufficient to use 4 equivalents, and the reaction is carried out as mildly as possible at -80°C to the reflux temperature of the solvent. The optically active alcohol and protected form of formula (13, (II)) of the present invention can be synthesized by oxidizing the compound of formula (m), (IV) by the method of the present invention, and further reacting with a nucleophilic reagent. , can be selectively induced into compounds [■], [■] as shown in the following reaction formula. (m) (1) 0x [■] (IVI (n) C In the formula, R1 has 1 to 1 carbon atoms. 10 substituted or unsubstituted alkyl groups or substituted or unsubstituted phenyl groups, and R4 and RS are not the same.) Here, R'' of R'M of the nucleophile is a hydrogen atom. , represents a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, or substituted or unsubstituted phenyl group having 1 to 10 carbon atoms, and M is Li, Na, K, Mg, respectively.
, Ca, Ti, Zr, Ni, Cu, Zn, Ajl, Sn
Indicates a metal selected from or a group containing the metal. Specifically, as R'M, R'Li, R'MgBr, R'MHI
,(R'),CuQLi,,R'CuQLi,(R')
, CuQLiMgBr, R'CuQMgBr, etc. However, Q represents a halogen atom, a cyano group, an alkylthio group, an arylthio group, or a thiocyano group. When reacting the above nucleophile R'M with compound [■] or (II), the nucleophile R'M is 0.5
It is preferable to use ~4 equivalents, particularly 0.8 to 1.2 equivalents. Further, a solvent can be used in the reaction, but any solvent used in the reaction may be one that does not inhibit the reaction, and examples thereof include tetrahydrofuran, hexane, bentane, diethyl ether, and the like. Note that the reaction temperature is usually -100 to 50°C, preferably -
The temperature is 80 to 0°C, and the reaction time is usually 5 minutes to 50 hours. As is already known, the reaction between the nucleophile R'M and the optically active alcohol of formula (I) or [■] can proceed stereoselectively. That is, R to the protected or unprotected hydroxyl group and carbonyl group in formula (13 or (II))
'The direction of the hydroxyl group produced by the reaction of M can be controlled to syn or anti. Obtained compounds [■], [■
] is induced into an ω chain that is useful as a synthetic intermediate for prostaglandin, which contains a secondary allyl alcohol having two consecutive asymmetric centers in its molecular structure, as shown in the reaction formula below. Ru. (In the formula, R@, R'l, R@, and Rs are each an alkyl group having 1 to 10 carbon atoms, and may be the same or different.) Specifically, the above (IK3 The following formula D is an example of a compound represented by the formula: (X) (XI) CXI) OSi(CH.). The compound is . N. It can be used in combination with mexiprostil (M1xprost11) by the method of Kolb et al. (Tatrahedron Latt. 2).
9, 6769, (1988)). As explained above, the general formulas (I) and (II) of the present invention
) and its protected forms are novel compounds containing various physiologically active substances, especially secondary allyl alcohols having two consecutive asymmetric centers in the molecule. Alcohol is useful as a synthetic intermediate for bioactive substances such as prostaglandins, and alcohol itself acts as a physiologically active substance. Moreover, according to the manufacturing method of the present invention, (1), (I
I) An optically active ketoallyl alcohol having a silyl group at the γ-position of the formula and its protected form can be optionally prepared with high optical purity and high stability. It can be combined with good selectivity. The present invention will be specifically explained below with reference to Examples and Reference Examples, but the present invention is not limited to the Examples below. In each example, Me represents a methyl group and n-Bu represents an n-butyl group. [Reference Example 1] 30H 2) Under water cooling, compound (1) (6.44 g, 26.4 mmal
Ethyl vinyl ether (5.05 d, 52.8 mmol) and viridium p-toluenesulfonic acid (approximately 300 q) were added to a solution of 1) in methylene chloride (50 d). After raising the temperature to room temperature and stirring for about 4 hours, saturated NaHCO, aqueous solution (150 d) was added. The organic layer was separated, the aqueous layer was extracted with hexane (50d), and the obtained organic layer was extracted with M g S
Dry with O4. ? After 7 tons had passed, the solvent in the furnace liquid was distilled off under reduced pressure to obtain 8.47 g of a crude product of compound (2).
This was used as is for the next reaction. The crude compound (2) (8.47 g) was dissolved in dimethyl sulfoxide (50id), and n-Bu4 was dissolved at room temperature.
NF (34.8 ml, 1 molar solution in THF, 34.8 m
mall) was added. After stirring at room temperature for 12 hours, saturated brine solution (150d) was added, and hexane (2X100
Extracted in step d). The organic layer was dried with MgSO, and after passing through the oven, the oven solution was distilled off under reduced pressure to obtain the crude product of compound (3) (approximately 9
g) was obtained. Purified by silica gel column chromatography to obtain compound (3) (5.48 g, 2
2.4 mmoffi) was obtained in a yield of 85%. [Reference Example 2] (3) (4) Under an argon atmosphere, add L to dry tetrahydrofuran (THF).
IAIH. (4 3 4 N, 1 1.4 mmo
After adding Jl) and cooling to O℃, compound (3)・(2.7
8g, 1 1. 4 wmofi) of THF (10
all) solution was slowly added dropwise. After stirring for 30 minutes, O
Water (approximately 0.7°C) was slowly added at ℃. followed by Na
F (6 g) and Celite (6 g) were added in order, and the mixture was stirred at room temperature for 30 minutes. When the m solution was filtered through Celite and the rp solution was collapsed under reduced pressure, compound (4) (2.7 8
g, yield ~100%) was obtained. (Example 1) CH. (J, (30d)
Oxalate chloride (0.96m, 10.9mmo
ffi) and, without stirring, add dimethyl sulfoxide (
1-56d, 21-9gtmoJl) was slowly added dropwise. After stirring for 5 minutes, CH of compound (4) (1.35 g, 5.49 mmon) obtained in Reference Example 2
．． C. (10d) solution was added dropwise and stirred for 15 minutes. Next, triethynoleamine (6,llIl!,
44 ■ won) was added dropwise and the temperature was reduced to zero over 1 hour without stirring.
The temperature was raised to ℃. After adding saturated brine (50d) and extracting twice with hexane (40d), the organic layer was dried over MgSO. After the RP filtration, the solvent of the RP liquid was distilled off under reduced pressure and the resulting crude product was dissolved in hexane (40+all), and a small amount of precipitate was generated. Furthermore, after filtering in a furnace using a small amount of silica gel to remove the precipitate, the solvent in the furnace liquid was distilled off under reduced pressure, and almost pure compound (5) (1.3 2
g, yield 99%) was obtained. In addition, this compound <5
) was used as is in the next reaction. The characteristic values of compound (5) were as follows. “HNM
R (CCI,,PRH): 60.14 (s, 9H), 0.98-1.40
(w+, 68), 2.00(ss, 3H), 3
．． 15-3.90 (j 2}1), 4.19 and 4.
35 (Zd, J=4.0Hz and J=3.8Hz,
IH), 5.57-6.23 (m, 2H) I R
(neat): 2950, 1710, 1240, 1080, 5
03-'R f =0.47 and 0.52 (hexane/ether = 2/1.2 diastereomer mixture)
[Reference Example 3] In an argon atmosphere, n-BuMgBr (5
．． 7 aQ, 1.05N solution in THF, 5.9 7
THF (5-) was added to mmojl), cooled to -78°C, and compound (5) (9 7 01113.9
A THF (6-) solution of 8 mmon) was slowly added dropwise. Furthermore, after stirring for 30 minutes at -78°C, about 1
．． The temperature was raised to 0°C over 5 hours. Saturated salt solution (30d)
, saturated NH, Ct aqueous solution (10d) was added, and then extracted twice with hexane (20d). The obtained organic layer was mixed with MgS
After drying at
The crude product of JI) was obtained in a yield of 83%. [Reference Example 4] (5) (6) OH Under an argon atmosphere, compound (6) (1,OOg,3.
A solution of 29 mgioffi) in THF (10 mQ) was cooled to 0°C, and a solution of NaH (paraffin-free, 158 mg, 6.58 mmon) was cooled to 0°C.
), then methyl iodide (0.31 mjn
, 4. 94 mmall) was added thereto, and the mixture was stirred at room temperature for 12 hours. Next, saturated brine (20d) was added, and after extraction with hexane (30d), the resulting organic layer was MgSO4
It was dried. After passing through the furnace, the solvent in the furnace solution was distilled off under reduced pressure to obtain compound (7) (1.0 2 g). Next, this compound (7) was dissolved in methanol (20d), p-toluenesulfonic acid (~30d) was added, and after stirring at room temperature for 30 minutes, saturated NaHCO, aqueous solution (40d) was added.
d) was added and extracted twice with hexane (20d). The obtained organic layer was dried with MgSO4, filtered, and the solvent of the furnace solution was distilled off under reduced pressure, resulting in the crude product of compound (8). I got something. When this was purified by silica gel column chromatography, compound (8) (650, 2
．． 83msall) was obtained in a yield of 86% (2 steps). The characteristic values of compound (8) were as follows. “HNM
R (CCL, PhH): δ0,13 (s, 9H), 0.96 (t, J
=6.6Hz, 3H), 1.03 (s, 3H),
1.15-1.74 (+*, 6H), 2.33
(brg, LH), 3.17 (s, 3H),
3.94 (tt J=1.8Hz, II{), 5
．． 78-6.02 (m, 2H)”CNMR (CD
C.J.I. ): δ143.7, 132.3. 7g. 9, 77.2
, 48.9, 33.3, 24, 8, 23.1,
17,6, 13J, -1.5I R (neat)
: 345G. 2950, 1620, 1250, 8
40cs-” (α) F: +26-4 (c 1
-5L C H C et al) m p . : 31.5-
-32.0°C (acicular crystals) [Reference Example 5] Compound (8) <24 0111: - 0.9 8ms
*ojl) CH. CD. Solution (5d) contains t-butylhydride peroxide (5.07M, CH, CI!, solution, 0.39d, 1.96 mmojl) and vanadium oxide acetylacetonate (V O (acac)a) (
After adding 10 mg), the mixture was stirred at room temperature for 3 hours. Additional V O (acac), (10 mg) was added to this mixture and stirred for 5 hours, then dimethyl sulfide (0.
5d) was added and stirred for 1 hour. N a H C O
Add s aqueous solution (20d) and hexane (30mQ),
Separate the layers and add the aqueous layer to hexane (20d)
Extracted with. These organic layers were dried with MgSO4 and concentrated, and the resulting crude product was subjected to silicage gel column chromatography. Compound (9) (225
0.865 oO was obtained with a yield of 88%. The characteristic values of the obtained compound (9) were as follows.

'HNMR (CC,, PhH): 60.12 (s, 9N), 0.98 (tt J
-6.0Hz, 3H), 1.21 (s, 3H),
1.17-1.82 (+a, 6H), 2.09
and 2.11 (2d, J=3.6}1z and J=3
．． 6Hz, LH) -2.37 (brs, LH),
2.72 and 2.86 (dd, J=3.6,6.
0Hz and J=3.6, 6.0Hz, IH), 3
．． 12-3.40 (m, IH), 3.19 (s,
3H) I R (neat): 3440, 2950, 1460, 1380, 1250,
1070.815am-1 R f : 0.22 and 0.11 (hexane/Et
20=3/l, diastereomer mixture) [Reference Example 6] (9) (10) Compound (9) (220g, 0.846mmoffi
) in THF solution (3d) with LDA (diisopropylamine (0.47d, 3.38mmall) and n-
A THF solution (3d) of butyllithium (n-BuLi) (1.1d, 2.31 molar solution in hexane, 2.54 mmoffi) was added at 0°C. After 10 minutes, n-Bu3SnH (0.2 7m,
Add 1.0 2 mmon), warm to room temperature, and add 3
Stir for hours. Salt solution (20d) and hexane (20d)
was added to separate the organic fraction, and the aqueous layer was diluted with hexane (20
Extracted in step d). These organic layers were dried with MgSO4 and concentrated, and the resulting crude product was subjected to silica gel force column chromatography, resulting in compound (10) (
348■, 0.755ms+offi) with a yield of 89%
Obtained with. The characteristic values of compound (10) were as follows. 'HN
R(C(J,,Me4Si):60.40-2.00
(m, 39H), 2.18 (d, J=3.0H
z), 3.17 (s, 3H), 3.96 (dd
, J=3.0, 5.4Hz, IH), 5.92
(dd, J=5.4.21Hz, IH), 6.
16 (d, J=21Hz, IH) CNMR (CDC): δ146.2, 130.8, 78.9, 78.0
, 4B. 7, 33.2, 21S. 9, 27.0,
24.8, 23.1, 17.4, 13.8,
13.4, 9.3 I R (neat): 3450, 2930
, 1465, 1380.10703-'? α〕■+14.6” (c 2.01, CHC prisoner,)

Claims (1)

[Claims] 1. The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] and the following general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... ...[II] (In the formula, R^1, R^2, and R^3 each have 1 to 1 carbon atoms
10 substituted or unsubstituted alkyl groups or substituted or unsubstituted phenyl groups, which may be the same or different from each other, and R^4 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or an unsubstituted phenyl group, and X is a hydrogen atom or a hydroxyl group-protecting group. ) An optically active alcohol having a silyl group at the γ-position. 2. The following general formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III] Or the following general formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[IV] ( In the formula, R^1, R^2, and R^3 each have a carbon number of 1 to
10 substituted or unsubstituted alkyl groups or substituted or unsubstituted phenyl groups, which may be the same or different from each other, and R^4 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or an unsubstituted phenyl group, and X is a hydrogen atom or a hydroxyl group-protecting group. ) The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] or the following general formula [II] ▲Mathematical formulas, chemical formulas, tables, etc. There are tables, etc. ▼... [II] (However, R^1, R^2, R^3, R^4, and X in the formula are each the same as above.) At the γ position shown by A method for producing an optically active alcohol having a silyl group.