JPS5812264B2 - Synthesis method of middle ring ketone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for synthesizing a middle-ring ketone having an 8- to 12-membered ring.

In recent years, the synthesis of macrocyclic compounds including macrolide antibiotics has attracted attention, and many studies have been reported.

Progress is being made in methods for synthesizing macrocyclic lactones as an essential step in promoting these synthetic studies.

On the other hand, there are many carbocyclic compounds having a middle ring in nature.

That is, not only seven-membered ring compounds but also taxanes (
Taxane), Ophioborane (Ophiobo
lane) skeleton is an 8-membered ring, caryofuran (Cary
opbyllane), Germacrane
ane ), Humulane and Cembrane skeletons are 9 and 1, respectively.
It is composed of 0-, 11- and 14-membered rings.

Possible methods for synthesizing the skeletons of these compounds include (1) cyclization, and (2) ring expansion or reduction, but for compounds with 10 or more members, ring formation is mainly performed by the former (cyclization reaction), and 9 Karyophyrene having a membered ring has been synthesized based on the latter (ring expansion method) ((a) M. Kodam
a, Y. Matsuki, S. lto, Tetrah
edron Lotters, 1121 (1976);
21st Natural Products Symposium (1978, Sapporo) Abstracts p. 4
33, (b) E. J. Corey, E., Hamanak
a, J. Am. Chem. Soca%89, 27 58
(1-967);Y. Kitagawa, A. l
toh, S. Haahimoto, ibid, 99
3864 (1977), (c) Masanobu Suzuki et al., No. 21
Annual Natural Products Symposium (1978, Sapporo) Abstracts p. 5 52
, (d)E. J. Corey, R. B. Mitra, H.
．． Uda, J. Am. Chem. , Soc. , Danhei, 4
85 (1964) etc.

]. However, it is generally considered that it is extremely difficult to form these intermediate ring skeletons by cyclization5, and it has been desired to establish a general intermediate ring and cyclization method.

Therefore, the present inventors conducted the above-mentioned method for synthesizing the middle ring skeleton.
As a result of intensive research, the present invention was completed by developing a method for easily synthesizing a middle-ring ketone with high yield.

The medium ring ketone obtained in the present invention is expected to be used as a raw material for converting into a natural product having the above-mentioned medium ring skeleton or as a raw material for a fragrance material.

The present invention will be explained below.

The starting material used in the present invention has the general formula that was first synthesized by the present inventors: (wherein, n represents an integer from 8 to 12).

), and is synthesized, for example, as follows (for the case where H=11).

In other words, 0-(methylamino)phenylmercabutane (3) (or its dimer (3)) was converted into triethylamine (E
When reacted with 10-bromodecanoic acid chloride (Br(CH2)tocOcl) in a mixed solvent such as tsN)-tetrahydrofuran (THF) or pyridine (Py)-THF,
Compound (4) or its dimer (4) is obtained almost quantitatively.

The crushed stone was treated with sodium ethoxide (EtONa)/ethanol (EtOH)-dioxane (Dioxane).
), sodium isopropoxide (i-PrONa)
/ inpropanol (i-PrOH) monodioxane, potassium t-butoxide (t-BuOK) / t-butanol (t-BuOH) monodioxane, sodium hydride (NaH) sodium borohydride (NaBH4
)/i-PrOH-dioxane, etc. solution dropwise at -70°C under a nitrogen atmosphere [high dilution method (high
method)) and one of the starting materials, lactam sulfide compound (5), is obtained in good yield.

This compound (5) was mixed with lithium diisopropylamide (L
After treatment with DA), reaction with methyl iodide (Mel) yields the methyl substituted product (6) of (5).

In a similar manner, n=s, 9, 10, 120 lactam sulfide compound (6), which is the starting material of the present invention, can be obtained.

The starting material (6) thus obtained was mixed with sodium periodate (Nal04), m-chloroperbenzoic acid (mC
PBA), when treated with a peracid such as peracetic acid, the general formula: (wherein, n is the same as above).

) is obtained in good yield.

The amount of peracid used is approximately 1.0 with respect to compound (6).
~1.1 equivalents are suitable.

These compounds are all new compounds.

In this reaction, it is preferable to use a solvent such as aqueous methanol or aqueous acetonitrile when using Nal04, chloroform or methylene chloride when using m-CPBA, or acetic acid or methylene chloride when using peracetic acid. The reaction temperature and reaction time are approximately 0 to 25°C, respectively.
Approximately 5 minutes to 40 hours is appropriate.

The obtained compound (7) was treated with a deprotonating agent such as lithium diisoprobylamide (LDA)-THF, potassium triphenylmethide ((C6H5)3CK))'THF, sodium methylsulfinylmethide (dimethylsulfoxide +
When the reaction is carried out at a reaction temperature of 0 to -50°C using dry ice-acetone etc. in the presence of NaH), the general formula: (However, in the formula, n is the same as above.

) is obtained almost quantitatively.

All of these compounds (8) are new compounds.

This compound (8) is used as it is in the next reaction without purification.

That is, compound (8) was directly mixed with THF-H20,
Dissolved in a solvent such as ethanol or acetone, Al-Hg,
Desulfurization reduction is carried out in the presence of Raney nickel, etc.

Appropriate reaction temperature and reaction time are approximately 50 to 80°C and approximately 1 to 8 hours, respectively.

In this way, a medium ring ketone (9), which is the object of the present invention, is obtained.

(However, in the formula, n is the same as above.

) Specific examples of the medium ring ketone (9) obtained in the present invention are as follows.

Next, the present invention will be explained by examples, but the present invention is not limited thereto.

Example 1 (n-8) Me of lactam sulfide (6) (n-8,490~)
Stir the OH (10 ml) solution and add Nal04 into it.
A solution of (416 mg, 1.1 eq.) in water (4.5 ml) is added dropwise.

After stirring at room temperature for 20 hours, the reaction solution was filtered and the slurry was filtered with CHC.
Extract with 13.

After drying the extract over MgSO, the solvent is distilled off and the resulting crude crystals are purified by chromatography over SiO2.

From the eluate of n-hexane AcOEt (1/2), lactam sulfoxide (power (n = 8) was 518 m as colorless crystals.
g (100% yield) was obtained.

When this is recrystallized from CHCl3-n-hexane, colorless prism crystals are obtained.

Physical properties of C(7) (n=8)] rap: 107-108°C NMR: δ1.19 (3H, d, j =6.
6Hz, CH-CH3) 2.9-3.3 (2H, rri, S CH2
)? ．． 3 5 (3H, S, N CHa)
7.96 ~ 8.20 (IH, m) Elemental analysis two-calculated value (0 16 H2 B NOS):
C, 6 5.4 9; H, 7.9 0; N
, 4.7 7; S, 10.93 Experimental value: ? ,65.36;H,7.88;N,4.74;3,1
1.03 (M of lactam sulfide (6) (n = 9, 410 mg) when n = 9, l
Add Nal04 (332~
, 1.1 equivalents) in water (3.5 ml), and the resulting crude crystals are purified by column chromatography on Si02.

Lactam sulfoxide (7) (n=9) was obtained as colorless crystals from the n-hexane AcOEt (1/1 to 1/2) eluate (yield 96.4%), and this was converted into CHC1
Recrystallization from 3-n-hexane yields colorless prism crystals.

(Physical properties of (7) (n=9)) mp: 104-106°C NMR: δ1.15 (3H, d-j=7Hz, CH-C
Ha) 2.65-3.00 (2H, m, SOCH2) 3.33
(3H,S,N-CH3) 8.0-8.3 (IH, m) Elemental analysis: Calculated value (CtH25NO2S): C, 66.
41; H, 8.20; N, 4.56; S, 10.43 Experimental value: C, 66.45; H, 8.20; N, 45.8; S, 1
0.37 (When n = 10, 1) Nal04, (33
6771, 1.1 equivalent) in water (3.5 m/), and the resulting crude crystals were subjected to column chromatography (n
= hexane-AcOEt (1/1 to 1/2)) to obtain 4121v (yield 89.8%) of lactam sulfoxide (7) (n=10) as colorless crystals.

(Physical properties of (7) (n=10)) mp: 144-145°C (recrystallized from CHCI3-n-hexane, colorless prismatic crystal) NMR: δ1.15 (3H, d-j=7Hz, CH- C
H3) 2.4-2.9 (2H, m% SOCH2) 3.36-3
．． 51 (3H, S, N-Me) 8.0-8.4 (IH,
m) Elemental analysis two calculated values (C, 8H2?NO2S); C, 67
．． 25; H, 8.47; N, 4.37; S, 9.97 Experimental value; C, 67.30; H, 8.44; N, 4.40; S, 9
．． 77 If Cn=11) then lactam sulfide (6) (n-11, 463rn9)
To a MeOH (9 ml) solution was added NalO4 (32
2 to 1.1 equivalents) in water (3.5d),
The obtained crude crystals were subjected to column chromatography (AcOE) using Si09.
t), lactam sulfoxide (n=11
) was obtained as colorless crystals at 430WI9 (yield 94.0%).

[(Physical properties of force (n-11))] mp: 117-118°C (colorless prismatic crystal recrystallized from CHC13-n-hexane) NMR: δ1.12 (d, 3H, d, J = 6.5Hz ，
CH-C Dan,) 3.24 (3H%S, N-CH,) 7.53-7.95 (IH, m) Elemental analysis: Calculated value (C1, H2, No2S); C, 68
．． 02; H, 8.71; N, 4.17; S, 9.56 Experimental value; C, 68.03; H, 8.74; N, 4.17; S; 9
．． 43 (n=12), Nal04 (2
97~, 1.1 equivalents) in water (3.5 ml), and the resulting crude crystals are purified by column chromatography on Si02.

From the n-hexane-AcOEt (1/1 to 1/2) eluate, lactam sulfoxide (7) (n=12) was obtained as a colorless powder (418~ (yield: 95.2%)).

[(Physical properties of force (n-12))] mp: 106-107°C (colorless powder purified from ether-n-hexane) NMR: δ1.16 (3H, d, j = 7Hz, CH-C
H3) 3.31, 3.43 (3] H, S, N-CH3) 7.8
~8.2 (IH1m) Elemental analysis: Calculated value (C20HatNO2S); C, 68
．． 73;H, 8.94;N, 4.01;・. S, 9.1
7 [General operating method] Ice-cooled dry THF (3 ml) in a stream of Ar (or N2)
i-PrNH (0.23 ml, 1.6 mmol) and then n-BuLi-n-hexane solution (1.6
After about 3 minutes, cool in a dry ice-acetone bath.

A solution of lactam sulfoxide (7) (0.5 mmol) in dry THF (2 ml) was added dropwise to this solution over about 4 minutes.
After keeping the same temperature for 30 minutes, change to a water bath and stir for an additional 30 minutes.

After cooling the reaction solution again in a dry ice-acetone bath, excess saturated aqueous NH4CI solution was added.

After neutralization with HCl, the reaction solution was . Extract with CHCl3.

The extract was filtered through a short Si02 ram and the solvent was distilled off to obtain crude ketosulfoxide (8).

(8) was dissolved in THF-H20 (9:1) (10 ml), and A made from aluminum foil (200 ~) was dissolved in this.
Add I-Hg and reflux for 6 hours in a N2 stream.

・Filter the reaction solution, extract the filtrate with CHCl3, filter the extract through a short column of Si02, and distill off the p solution to obtain a mixture of medium ring ketone (9) and disulfide (3). .

(If n=8, the At-Hg reduction reaction operation is repeated twice).

The above mixture was added with EtOH (10 ml), 2,4-dinitrophenylhydrazine (135 mg) and concentrated H2So4 (
5 drops) was added, refluxed for 20 minutes, and the crystals (
(9) (2,4-dinitrophenylhydrazone derivative) is collected in large quantities.

If necessary, the reaction solution is concentrated under reduced pressure, and the resulting residue is
Column chromatography using 02 (30F)? -de n-
From the hexane-AcOEt (4/1) elution part (9) 2
・4-DNP (dinitrophenylhydrazone) form can be obtained.

(For n = 8, l, 12-membered ring lactam sulfoxide (force ((n = s) 147
■, 0.5 mmol) from 8-membered ring ketosulfoxide (8
) (n=8) was obtained as a pale yellow oil (162 mg).

(Physical properties of (8) (n=8)) IR: vCC”3 30 0, 1 6 9 8c
In”NMR: δ 0.6 8 (d, j = 6.6 Hz) .8 (,, U = 7.2H2)} (CH-0dan・) 2,8
6, 2.96 (3H, S, N-CH3) 4.9 8 (I
H, dd, j = 3.6, 11.4 Hz, So-CH-
Co) When the obtained (8) (n=s, 162 mg) was reduced twice with Al-Hg, the 8-membered ring ketone (9) (n=8) and (3
A mixture of ) was obtained as a yellow oil (130 μm).

Physical properties of C(9) (n=s)] NMR: δ1.05 (3H, d, j=7, CH-CH3
) 2.71 (3H,S,N-CH3') From this mixture, the 8-membered ring ketone (9) (n = 8
)'s 2,4-DNP substance is 105 as an orange prism crystal.
(Yield: 65.6%)

[Physical properties of 2-4-DNP form of (9) (n = 8)] mp: 135-137° IR: νCCl43320, 1620, 1590, 13
35cm-1 Elemental analysis: Calculated value (C,, H28N404): C, 56
．． 24; H, 6.29; N, 17.49 Experimental value; C, 56.46; H, 6.30; N, 17.54 Mass spectrometry: m/e 320 (M+), 285 (M-35) ( 13-membered lactam sulfoxide (7) (n=9, 154
7Q, 0.5 mmol) to 9-membered ketosulfoxide (
8) (n-9) was obtained as a pale yellow oil (1891v).

(Physical properties of (8) (n = 9)) CCl4 lR: ν3320, 1698 cm-1 NMR: δ0.46 (3H, d, j = 6Hz, CH-C
H3) 2.84, 2.93 (3H, S, N'CHs) 4.88
(1H, dd, j=3, 10.8, SO-CH-CO) From the above (8) (ri=9, 189■), a 9-membered ring ketone (
9) A mixture of (n=9) and (3) produces a yellow oil (17
4-) were obtained.

(Physical properties of (9) (n=9)) NMR: δ1.07 (3H, d, .j=7, CH-CH
3) From this, 9-membered ring ketone, (9) (n=9) 2.4-D
The NP form is orange needle-like crystals with a yield of 106η (from (7), the yield is 6
3.5%) was obtained.

(Physical properties of 2-4-DNP form of (9) (n=9))
mp: 120-122° Elemental analysis two calculated values (ClaH22N404); C157
．． 46; H, 6.63; M, 16.76 Experimental value: C, 56.99; H, 6.63; N 116.63 Mass spectrometry: m/e 334 (M+), 299 (M-35) (n= 10), a 14-membered ring, lactam sulfoxide (7) (n=10, 1
10-membered ring ketosulfoxide (8) (n=10) as a pale yellow oil (180
mg) obtained.

((8) (Physical properties of n=10) ?R: νCCl43320, 1695 cm-1 NMR:
δ0.54 (3H, d, j=6.6Hz, CH-CH3
) 2.87, 2.96 (3H, -S1N-CH3) 5.0
9 (1H, t, j = 7.2, SO-CH-CO) A mixture of 10-membered ring ketone (9) (n = 10) and (3) (160 mg) from the above (8) (n = 10, 180 mg)
) was obtained as a yellow oil forest product.

Physical properties of C(9) (n=1o)] NMR: δ1. o5(3H, d, j=7Hz, CH-C
H3) 2.79 (3H,S,N-CH3) From this, 2.4- of the 10-membered ring ketone (9) (n=10)
The DNP substance is an orange powder (129In9, yield 7 from (7)
4.1%).

(Physical properties of 2-4-DNP form of (9) (n=10)) ynp: 99101° Elemental analysis: Calculated value (CtH24N404): C, 58.
61; H, 6.94; N, 16.08 Experimental value: C, 58.30; H, 6.93; N, 16.06 Mass spectrometry: m7e34.8 (M+) (15 members when n = 113 Cyclic lactam sulfoxide 7 (n=11, 168η
, 0.5 mmol) to 1 l-membered ring ketosulfoxide (8
) (n=11) was obtained as a pale yellow oil (196~).

Physical properties of C(8) (n=11)] ■R: νCCl433001697cm-1NMR:δ
0.38C3H, d, j = 7Hz, CH-CH3) 2,79, 2.87 (3H, S, NCHs) 4.6-4
．． 9 (IH, m, SOC Dan-CO) (8) above (n=1
1,196 da) from 11-membered ring ketone (9) (n=11)
A mixture of (165~) and (3) was obtained as a yellow oil.

(Physical properties of (9) (n = 11)) NMR: δ1.04 ('3H, d, j = 7Hz, CH-
CH3) From this, the 11-membered ring ketone (9) (n=IB of 2,4-
DNP is an orange prismatic crystal (176 ~, (yield 97 from force)
．． 2%).

((9) (Physical properties of 2-4-DNP substance with n = 1 1) mp: 121-123° CCI ■R: ν 43320, 1620, 1590, 133
5cm' Elemental analysis: Calculated value (C1s H26 N4 04)
:C15 9.6 5 ;H, 7.2 3 ;N
, 1 5.4 6 Experimental values: C, 5 9.1 6 ; H, 7.0 2 ; N,
1 5.3 5 Mass spectrometry: m/e 3 6 2 (M
) [n-12] 16-membered ring lactam sulfoxide (7) (n=i2, 17
5 to 0.5 mmol), 12-membered ketosulfoxide (8) (n-12) was obtained as a pale yellow oil (209 to).

[Physical properties of (8) (n=12)] IR: νCCl43310, 1707-1700 maX cm-1 NMR: δ0.5 1 (3H, d, j =
7.2Hz, CH-CH3) 2.84, 2.93 (3H, 31N-CM3) 5.00
(IH1dd,j=4.2, 7.2 Hz 1SO-
CH-CO) From the above (8) (n-12, 209-), a mixture of 12-membered ring ketone (9) (n=12) and (3) (215-) is obtained as a yellow oil.

NMR: δ1.05 (3H, d, j=6.5Hz,
CH-CH3) From this, the 2,4- of the 12-membered ring ketone (9) (n-12)
DNI) body is an orange plate-like crystal (130~, yield 6 from (7)
9.1%).

Physical properties of 2-4-DNP form of C(9) (n=12)] mp: 1 7 1~175° Elemental analysis two calculated values (C1, H28N404); C,
60.62;H, 7.50;N, 1 4.8
8 Experimental values: C, 60.49; H, 7.51; N, 14.78 Mass spectrometry: m/e 376 (M+), 341 (M
-35)

Claims (1)

[Claims] 1. A lactam sulfide compound represented by the general formula: (wherein n represents an integer of 8 to 12) is treated with 1.0 to 1.1 equivalents of peracid. General formula: (However, in the formula,
n is the same as above. ) is obtained, and this is treated with lithium diisopropylamide to obtain a compound represented by the general formula: (wherein, 'n is the same as above), and this is treated with a reducing agent. After desulfurization and reduction, the general formula: ′ (However, in the formula,
n is the same as above. ) A method for synthesizing a middle-membered ring ketone, which is characterized by obtaining a middle-membered ring ketone represented by