Note: Descriptions are shown in the official language in which they were submitted.
~7~35~3
TOTAL SYNTHESIS OF THE UTERO-EVACUANT
SUBSTANCE D,L-ZOAPATANOL
The zoapatle plant is a bush about 2 meters
high that grows wild in Mexico. Botanically, it is
known as Montanoa tomentosa according to Cervantes, Fam.
Compositae, Tribe Heliantheae; another variety o the
. .
species is Montanoa florlbunda. The plant is described
in great detail in Las Plantas ~edicinales de Mexico,
Third Edition, Ediciones Botas ~1944).
The plant has be4n used for centuries in the
form of a "tea" or other crude aqueous preparations
pr.imarily as a labor inducer or menses inducer for
humans. Its use as a utero-evacuant has been documented
in the literature.
In U.S. Patent No. 4,086,358, a method is
described ~or the isolation of the active ingredients
in the zoapatle plant. One of the active ingredients
is 2S, 3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-
dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol. This compound,
referred to as zoapatanol, has the following structural
formula:
~0,~
~~0
c~3
The present invention relates to a method for
the total synthesis of 2S*, 3R*-6~-(2~hydroxyethy].idene)-
[*The asterisk indicates the xacemic nature of the compoundand refers to the relative configuration of the ~ ral centers.]
'
7~35~3 -
2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.
Many of the intermediates employed in the synthesis of
zoa~atanol are novel compounds and are included as
part of the invention.
The synthesis is comprised of several steps
which are summarized in the following schematic diagram:
M M
Br Mg ~ ~ ~ MgBr
(1) ~ (2)
~ OH
TH ~ ~ ,OH
~ O
r ,-OH OH
~_ U IlG~r~
R20/PYr i1`
OR
(4)
M RO", ~ OR~ RO ~ OR
~ ~oJ ~ ~J
CH3 CH3
~6) t7)
H~
,~
" " . .
(8)
~L~7~3s~3 `
RO" ~ OR RO, ~ OR
(6) ~ ~ J CrO3- ~SO4 ~ 0 J
(8) (9)
~Hydrolysis
O ~", ~ OH
~OJ
CH3
(1 0 )
Wherein M is a protecting group selected from
the group consistinq of an O-tetrahYdropyranyl qrou~ and
an O-ethoxyethyl group, R is an acyl group having 2-5
carbon atoms and X is selected from the group consist-
ing of bromo, chloro, iodo, tosyl, mesyl and brosyl.
As seen rom the diagram, the first step in
the synthesis involves the preparation of the Grignard
reagent (2) from the corresponding halo compound
8-bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy),-
2-octene (1). For purposes of describing the invention,
the process will be described using a 2-tetrahydropyranyl
group as the protecting group. The reaction with
magnesium is carried out in the standard fashion,
pre~erably in an organic solvent such as ether or
tetrahydrofuran. The Grignard reagent is preferably
uced in the next step without isolation.
The coupled product ~3) is prepared by reacting
the Grignard reagent with a substituted 6,7-oxido-2-
octen-l-ol. The reaction is carried out in an organic
solvent such as ether or tetrahydrofuran at a temperature
between about -20 and 0C. It is preferred to carry out
7~3~8
the reaction In the presence of a catalytic amount of a
copper salt such as, ~or example, cuprous iodide,
cuprous bromide and lithium copper chloride. The
coupled product ~3) can be used directly in the
cyclization step or it can be purified first by convert
ing it to the diacyl deri~ative (4) by reaction with a
suitable acylating agent such as acetic anhydride in a
base such as pyridine.
The product obtained from the coupling reaction
(3) is then converted to a mixture of epimeric oxepanes
(5) upon treatment with a catalytic amount of a Lewis acid
such as boron trifluoride etherate, alumlnum chloridel and zinc
chloride, for example, or a protic acid such as ~-toluenesulfonic
acid and trifluoroacetic acid. l~e reaction may be carried out
in an organ~c solvent such as ether or tetrahydrofuran,
for example, at a temperature between about 0 and 30C.
The mixture of oxepanes can also be prepared from the diacyl
derivative (4) by ~irst hydrolyzing the ester groups~ith
a mild base such as potassium carbonate, for example, and
then reacting the product of the hydrolysis with a Lewis
acid.
The mixture of epimeric oxepanes (5) is converted -
to a mixture of diacyl derivatives (6 and 7) by reaction
25 with an acylating agent such as, for example,acetic anhydride,
propionic anhydride or butyric anhydride and acyl halides,
such as for example, acetyl chloride, propionyl chloride
and butyryl chloride in a basic medium such ~s pyridine.
The mixture o~ diacyl derivatives i5 separated by physical
means prior to the next step. A preerred method o~
Reparation is preparat~e thin layer chromatography on
a suitable adsorbent such as silica gel, alumina or
35 10risil~ However~ any suitable method of separating the
epi~erlc compounds may be employed. Other suitable
methods include column chromatography and high pressure
liquid chromatography. The compounds are epimeric at
the 3-position.
~ .. -
~7~3~;8
Hydrolysis o~ the tetrahydropyranyl deriva-
tive (6) to the hydroxyl compound (8) is accomplished
by treating the tetrahydro;~yranyl deri~at~ve with an
acidic solvent system. Suitable acidic solvent systems
include tetrahydrofuran-water-acetic acid, acetonitrile-
water-acetic acid, and tetrahydrofuran water-sulfuric
acid.
The acylated derivative (8) is then converted
to the derivatized utero-ev~cuant material (9) ~y treat-
ment with a suitable oxidizing agent such as, for example,chromium trioxide-sulfuric ~cid, chromium trioxide-acetic
acid or chromium trioxide-pvridine. The oxidation is pre-
ferably carried out in a suitable organic solvent such as
acetone, 2-butanone, chloroform or methylené chloride.
The particular solvent employed will depend upon the
particular oxidi~ing agent employed in the oxidation step.
The residue o~tained from the oxidation reaction is then
converted to the underivatized utero-evacuant material (10
by hydrolysis with a suitable base such as, for example,
sodium hydroxide, potassium hydroxide, potassium carbonate
and tetra n-butyl ammonium hydroxide. The hydrolysis step
is preferably carried out in an organic solvent such as, fox
example, methanol, ethanol, isopropanol, benzene, ether and
tetrahydrofuran. However, aqueous media may also be employed
for the hydrolysis step. The reaction is preferably carried
out in an inert atmosphere such as, or example, nitrogen or
argon. The reaction is generally carried out at room
temperature al~hough elevated temperatures such as the
re1ux temperature of the solvent~ for example, may also
be employed. The crude product of the hydrolysis can be
further purified by column chromatography oYer an adsorbent
material~ such as silica gel, alumi:na or Florisi ~
The bromo compound,8-bromo-2,6-dimethyl-5-~2-~ .ra-
hydropyran-2-yloxy?j-Z-octene,used to prepare the Grignard
reagent in the first step in the synthesis is prepared by a
~1~';'
~g3S~ '
series of reacttons using 5~bromo-2-methyl-2-pentene
as the starting material, The bromide is first converted
to 2-methyl-5-nitro-2-pentene by reaction with sodium
nitrite in dimethylsulfoxide.The nitro compound is then
reacted with methyl crotonate to form methyl 3,7-dimethyl-4-
nitro-6-octenoate. Reaction of the octenoate derivative
with titanous chloride results in the formation of the oxo
compound, methyl 3,7-dimethyl-4-oxo-6-octenate. The oxo
compound is then reacted with lithium aluminum hydride
10 to form 3,7-dimethyl-4-hydroxy-6-octen-1-ol. The diol is
converted to the mono-acetate by reaction with acetic anhydride
and the mono-acetate is then converted to the tetrahydro-
pyranyl derivative by reaction with dihydropyran. The
tetrahydropyranyl derivati~e is converted to the corresponding
15 alcohol by reaction with potassium carbonate in a mixture
of methanol and water. The bromo compound is then obtained
by reacting the alcohol 3,7-dimethyl-4-[Z~tetrahydropyran-2-
yloxy)1-6-octen-1-ol with phosphorous tribromide or tri-
phenylphosphine and carbon tetrabromide.
The substituted 6,7-oxido~2-octen-1-ol compound
employed to prepare the coupled product (3) is itself pre-
pared by a series of reactions using myrcene as the starting
material. 8-Hydroxy-7-methyl-3-methylene-1,6-(E)-octadiene
is first synthesized from myrcene by the method of G. Buchi
25 and H. Wuest, Helv. Chim. Acta, 50,2440 (1967). The
octadiene compound is then converted to the hydroxy epoxide
by xeaction with a peracid such as m-chloroperbenzoic acid
or peracetic acid. The hydroxy epoxide is then converted to
the diac~l derivative by reaction with an e~uivalent amount
30 of a halogen~ such as bromine~ followed by an excess of an
acetate salt, such as potassium acetate. The major product
of the reaction is the compo~md having the E configuration,
however~ about 20% of the compound hav~ng the Z configuration
is also formed, Treatment of the diacyl derivative with a
slight excess of ~-toluenesulfonyl chloride in the presence
llt7~33~ `
of a base affords the corresponding tosylate. Reaction
of the tosylate with potassium bromide or sodium
bromide in 2-butanone at reflux temperature gives the
corresponding bromo derivative. The tosylate or
the bromide derivative is then hydrolyzed to
the diol, 7-methyl-3-hydroxymethyl-6,7-oxido-8-
tosyloxy-(E)-2-octen-1-ol or 7-methyl-3-hydroxymethyl-
6,7-oxido-8-bromo-(E)~2-octen-1-ol by treatment with
a base such as sodium hydroxide, potassium carbonate
or tetra-_-butyl ammonium hydroxide. During the
workup of the reaction mixture, the compound having
the Z configuration forms a complex with magnesium
sulfate which results in a product having only the
E configuration. Those compounds wherein X is brosyl
and mesyl are prepared in the same manner in which
the corresponding tosylate is prepared except
that p-bromotoluenesulfonyl chloride and methane-
sulfonyl chloride are employed in place of
~-toluenesulfonyl chloride. The compound (1)
wherein M is O-ethoxyethyl is prepared in the same
manner as the compound wherein P~ is O-tetrahydro-
pyranyl except that ethyl vinylether is employed
in place of dihydropyran. --
The following examples describe the
invention in greater detail and are inten~ed to
be a way of illustrating and not limiting the
invention.
~L~7935~
EXAMPLE I
8-Hydroxy-7~methyl-3-methylene~6,7-oxido-1-octene
A solution of sodium acetate (25 g, 0.03 m)
in 40%peracetic acid (85 ml) is added to a mixture
of 8-hydroxy-7-methyl-3-methylene-1,6-(E)-
octadiene (50.0 g, 0.33 m), sodium carbonate (42.4 g,
0.40 m) and methylene chloride (500 ml) at 0.
The resulting mixture is allowed to come to room
temperature and is stirred for an additional hour
after which it is filtered/ diluted with methylene
chloride (1 1) and washed with 5~ sodium bicarbonate
(2 1). The organic layer is dried (Na2SO4), and
evaporated _ vacuo to give the crude product
(49.5 g).
The crude product is purified by column
chromatography on silica gel (600 g; ethyl acetate/
hexane 1:9) to give 8-hydroxy 7-methyl-3-methylene-
6,7-oxido-1-octene (23.2 g, 42%), ir (neat): 3448,
-1
1592 cm
nmr (CDC13) ~ : 1.25 (s, 3H, CH3-C~-,CH), 3.03 (t, J=6
Hz, lH, /~-,CH), 3.56 (s,2H,-CH2-OH), 4.90 - 6.58
(m, 5H, ~=~H2, -CH=CH2).
EX~MPLE 2
l-Ac toxy-8-hydroxy-7-methyl-3-acetoxymethyl~-6_7-
oxido-(E~-2 octene
Bromine (56.8 g, 0.355 m) is added to a
solution of 8-hydroxy-7-methyl-3-methylene-6,7-oxido-
l-octene (59.7 g, 0.355 m) in methylene chloride (1 1)
under nitrogen at 0. The resulting mixture is allowed
to warm to room temperature and then washed with water
(500 ml). The oryanic layer is dried (Na2SO4) and the
solvent is removed to give the crude dibromide (117.0 g).
A portion of this crude dibromide (57.2 g) in
. .
31L~7935~3 `
EXAMPLE 2 (Cont'd)
carbon tetrachloride (50 ml) is added to a solution of
potassium acetate (59.8 g, 0.61 m) and adogen 464
(15.0 g) in water at 60. The resulting mixture is
stirred overnight, after which it is cooled to room
temperature, diluted with ether (1 1) and washed with
water (500 ml). The organic layer is dried (Na2SO4) and
evaporated in vacuo to give crude diacetate (64.0 g).
The crude product is further purified by column
chromatography on silica gel (2 kg, ethyl acetate/hexane
4:6) to give 1-acetoxy-8-hydroxy-7-methyl-3-acetoxymethyl-
6,7-oxido-(E)-2-octene (9.5 g; 18~).
ir (neat) 3484, 1730 cm 1; nmr (CDC13)S: 1.28 (s, 3H,
~ ~ Q
CH3-C--CH), 2.05 and 2.07 (each s, 6H, CH3-C-O-), 3.00
(t, J=6 Hz, lH, -C--CH), 3.58 (bs, 2H, -CH2-OH), 4.50-
4.73 (m, 4H, ~C=CHCH2OAc and ~ C=C-CH2OAc), 5.63 (t,
J-7 Hz, lH,,JC=CHCH2OAc).
EXAMP~E 3
l-Acetoxy-7-methyl-3-acetoxymethyl-
6,7-oxido-8-tosyloxy-(E)-2-octene
Triethylamine (10 ml) and tosyl chloride
~13.78 g, 0.072 m) are added to a solution of l-acetoxy-
8-hydroxy-7-methyl-3-acetoxymethyl-6,7-oxido-(E)-2-
octene (10.34 g, 0.036 m) in dry tetrahydrofuran (300 ml).
The resulting mixture is stirred at room temperature
under nitrogen for 6 days. The mixture is then diluted
with ether t800 ml) and washed with 5% sodium bicar-
bonate (800 ml) and water (800 ml). The organic layer
is dried (Na2SO4) and evaporated ln vacuo to give the
crude product (18~3 g). The crude material is purified
by column chromatography on silica gel (600 g; ethyl
acetate/hexane; 40:60) to give 1-acetoxy-7-methyl-3-
acetoxymethyl-6,7-oxido-8-tosyloxy-~E)-2-octene (10.12 g,
64%).
3SI~ ~
EXAMPLE 3 (Cont'd)
ir (neat) 1730, 1595 cm 1; nmr (CDC13)~: 1.23 (s, 3H,
CH3-C\--CH), 2.03 and 2.07 (each s, 6H, C_ 3-C~o )~ 2.43
(s, 3H, CH3 ~ )~ 2.78 (t, J=6 Hz, lH, ~ -CH), 3.90
o
(s, 2H, -CH2OTs), 4.47 - 4.70 (m, 4H, ~C=CH-CH2OAc and
~ C=C - CH2OAc), 5.62 (bt, J=6 Hz, lH, C=C~cH OAc)
EXAMPLE 4
7-Methyl-3-hydroxymethyl-6,7-oxido-8-tosyloxy-
(E)-2-octen-1-ol
A mixture of l-acetoxy-7-methyl-3-acetoxymethyl-
10 6,7-oxido-8-tosyloxy-(E)-2-octene (4.0 g, 9.1 mmole),
methanol (150 ml), water (5 ml) and saturated po~assium carbonate
solution (5 ml) is stored at room temperature for 2 hours. ~ost of
themethanol is then removed m vacuo and the resulting mixture is
extracted wlth ethyl acetate (3x20 ml). The ccmbined organic
15 layer is dried (MgSO4) and evaporated ln vacuo to give
an oil (3.4 g). The crude oil is further purified by
column chromatography on silica gel (20 g, isopropanol/
chloroform 2:98) to give 7-methyl-3-hydroxymethyl-6,7-
oxido-8-tosyloxy-(E)-2-octen-1-ol as a colorless oil --
(2.24 g, 69%).
ir (neat) 3424, 1597 cm 1; nmr (CDC13)~: 1.28 (s, 3H,
CH3-C--CH), 2.43 (s, 3H, CH3 ~ ), 2.83 (t, J=6 Hz,
~C ~ H)' 3 90 (s, 2H, -CH2-OTs), 5.70 (bt, J=6 Hz, lH,
o
=f-~H2-OH)~
H
EXAMPLE 5
2-Methyl-5~nitro-2-pentene
5-Bromo-2-methyl-2-pentene (120 g, 0.736 m) is
added dropwise to a solution of sodium nitrite (60.9 g,
0.883 m) in dimethylsu~oxide (700 ml) at room temperature
under nitrogen. The mixture is stirred for 1 hour and
....
~7913S8
EXAMPLE 5 (Cont'd)
treated with water (500 ml) and petroleum ether (1 1).
The organic layer is dried (Na2SO4) and evaporated in
vacuo to give a pale yellow liquid (80.7 g). This
material is purified by column chromatography on silica
gel (800 g, petroleum ether) to give 2-methyl-5-nitro-
2-pentene as a colorless liquid (45.4 g, 48~).
ir (neat) 1550 cm 1; nmr (CDC13)S: 1.70 and 1.73 (both
s, 6H, (CH3)2-C=C ), 2.50^-2.93 (m, 2H, -CH2-N02),
4.35 (t, J=8 Hz, 2H, -CH2-CH2-NO2), 5.05 (bt, J=7
Hz, lH, ~C=CH).
EXAMPLE 6
Methyl 3,7-dimel~yl-4-nitro-6-octenoate
1,5-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is
added to a solution of 2-methyl-5-nitro-2-pentene
(25.0 g, 0.193 m) in methanol (200 ml). The resulting
mixture is heated to 60 and methyl crotonate (30.85 g,
0.308 m) is added under nitrogen. The mixture is then
stirred for 6 days at 60 after which it is cooled to
room temperature and most of the methanol is removed
_ vacuo. The residue is treated with ether (500 ml)
and washed with 2N HCl (250 ml) and water (250 ml).
The organic layer is dried (Na2SO4) and evaporated
ln vacuo to give 42.~ of crude product. The crude pro- --
duct is purified by column chromatography on silica gel
(500 g, ethyl acetate/h~xane 2:98) to give methyl 3,7-
dimethyl-4-nitro-6-octenoate (8.65 g, 42~).
ir ~neat): 1736, 1547 cm 1; nmr (CDC13)~: 1.62 and 1.68
(both s, 6H, (CH3)2C=CH), 3.67 (s, 3H,-OCH3), 4.22-4.42
(m, lH, CH-NO2),4.95 (bt, J=7 Hz, lH, ~ C=CH).
EXAMPLE 7
Methyl 3_7-dimeth~1-4-oxo-6-octenoate
A solution o methyl 3,7-dimethyl-4-nitro-
6-octenoate (24.55 g, 0~107 m) in methanol (10 ml) is
added dropwise to a solution of sodium methoxide
(6.37 g, 0.118 m) in methanol (250 ml) at room tempera-
ture under nitrogen. The mixture is stirred for 1 hour,
added to a mixture of 20~ titanous chloride (170 ml,
~ ~9~5~
EXAMPL~ 7 (Cont'd)
0.267 m) and pH 7 buffer (potassium phosphate monobasic-
sodium hydroxide buffer) solution (340 ml). The
resulting mixture is stirred for 30 minutes after which
it is treated with ether (1 1). The organic phase
is separated, dried (Na2SO4) and evaporated in vacuo
to give the crude product (15.4 g). This material is
purified by column chromatography on silica gel (300 g,
2~ ethyl acetate in hexane)to give methyl 3,7-dimethyl-
4-oxo-6~octenoate as a colorless liquid (6.8 g, 35~).
ir (neat) 1705 and 1735 cm 1; nmr (CDC13)~ : 1.15 (d,
J=7 Hz, 3H, CH3- ~H), 3.2 (bd, J=7 Hz~ 2H~
3.63 (s, 3H, CH30-), 5.30 (bt, J=7 Hz, lH, ~ CH-).
EXAMPLE 8
3,7-Dimethyl-4-hydroxy-6-octen-1-ol
Methyl 3,7-dimethyl-4-oxo-6-octenoate (6~ g,
34mmole) in ether (10 ml) is added to a mixture of lithium
aluminum hydride (1.3g, 34 mmole) and ether (150 ml) at 0.
After the addition is complete the mixture is allowed
to warm to room temperature and stirred for 1 hour,
after which it is cooled to 0 and carefully added to
a 5% aqueous sodium bicarbona~e solution (50 ml). The
resulting mixture is treated with water (100 ml) and
ethyl acetate (300 ml). The organic phase is separated,
dried (Na2SO4) and the solvent is removed ln vacuo to
give a colorless oil (50.6 g, 94~). This material
shows one spot on TLC ~silica gel 50% ethyl acetate in
hexane) and is not further purified.
ir (neat) 3225 cm 1.
EXAMPLE 9
8-Acetoxy-2,6-dimethyl-5-hydroxy-2-octene
A mixture of 3,7-dimethyl-~-hydroxy-6-octen-1-
ol (5.06g, 29 mmole), acetic anhydride (3.06 g, 30 mmole),
pyridi~e (4.75g, 60 mmole) and ether (100 ml) i5 stirred
at room temperature for 16 hours. The resulting mixture
is treated with ether (200 ml) and washed with saturated
~7~3S~
13
EXAMPLE 9 (Cont'd)
cupric sulfate solution (2xlO0 ml). The organic phase
is dried (Na2SO4) and evaporated ln vacuo to give
8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene as a colorless
oil (2.27 g, 45%).
ir (neat) 3508; 1738 cm 1; nmr (CDC13)~ : 0.93 (d, J=7
/~
Hz, 3H, CH3-CH), 2.0 (s, 3H, CH3-C-0-), 4.10 (t, J=7
Hz, 2H, -CH2-OAc), 5.10 (bt, lH, /C=CH).
EXAMPLE 10
8-Acetoxy-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-
2-octene
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy~
2-octene (2.27g, 10.6 mmole), dihydropyran (0.98 g,
11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic
amount) and ether (50 ml) is stirred at room temperature
for 16 hours. The resulting mixture is treated with
ether (150 ml) and washed with 5% sodium bicarbonate
solution (2xlO0 ml). The organic phase is dried (Na2SO4),
and evaporated in vacuo to give the crude product
(3.27 g). This material is further puriied by column
chromatography on silica gel (25 g, 5~ ethyl acetate
in hexane) to give 8-acetoxy-2,6-dimethyl-5-[2-
(tetrahydropyran-2-yloxy)]-2-octene as a colorless oil
(2.67 g, 89~). ,0
ir (neat) 1739 cm 1; nmr (CDC13)~: 2.07 (s, 3H, CH3-C~
4.61 tbr, lH, ~ 0/ ), 5.2 (br, lH, ~C=CH).
H
EXAMPLE 11
3,7-Dimethyl 4-~2-(tetrahydropyran-2-yloxy)]-
6-octen-1-ol)
A mixture of 8-acetoxy-2,6-dimethyl-5-[2-
(tetrahydropyran-2-yloxy)]-2-octene (2.67 g, 0.5 mmole),
saturated potassium carbonate solution (9 ml), water
793S~ ~
14
EXAMPLE 11 (Cont'd)
(6 ml) and methanol (100 ml) is stirred for 3 hours
at room temperature. Most of the methanol is removed
_ vacuo and the residue is treated with ethyl acetate
(500 ml) and water (200 ml). The organic phase is
dried (Na2SO4) and evaporated ln vacuo to give the crude
product ~2.5 g). This material is further purified
by column chromatography on silica gel (25 g, 15%
ethyl acetate in hexane) to give 3,7-dimethyl-4-
~2-(tetrahydropyran~2-yloxy)]-6-octen-1-ol as a
colorless oil (1.5 g, 60~).
ir (neat) 3434 cm 1, nmr (CDC13)~: 4.62 (br,LH, Q ~ )~
\ / H
5.2 (br, lH, ~C=CH).
EXAMPLE 12
8=Bromo-2,6-dimethyl-5-~2-(tetrahydropyran-
2-yloxy)]-2-octene
Triphenylphosphine (1.83 g, 7.02 mmole) in
methylene chloride (30 ml) is added to a mixture of
3,7~dimethyl-4-[2-(tetrahydropyran-2-yloxy)]-6-octen-1-
ol (1.20g, 4.7 mmole), carbon tetrabromide (1.94 g,
5.85mmole), pyridine (2 ml) and methylene chloride (30 ml)
at 0 under nitrogen. The mixture is allowed to warm
to room temperature and stirred for 4 hours, after which
it is treated with methylene chloride (100 ml) and
washed with 5~ sodi~m bicarbonate solution. The
organic phase is dried (Na2SO4) and evaporated in vacuo
to give the crude product ~5.6 g) This material is
~urther purified by column chromatography on silica gel
(100 g, ~% ethyl acetate in hexane) to give 8-bromo-
2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-2-octene
as a colorless oil (0~7 g, 46%).
nmr (CDC13)~: 4.61 (br, lH~ 5.15 ~br, lH,
/
/C=CH).
~,~
35~
EXAMPLE 13
3,7-Dimethyl-4-[2-(tetrahydropyran-2-
yloxy)]-6-octenyl magnesium bromide
The Grignard reagent is prepared from 8-
bromo-2,6-dimethyl-5-[2-(tetrahydropyran-2-yloxy)]-
2-octene (8.5g, 26.7 mmole) and magnesiumt650m~, 27.1 mmole)
in tetrahydrofuran (35 ml) at room temperature under
argon. The reagent is not isolated but is used directly
in the next step.
EXAMPLE 14
1-Acetoxy-3-acetoxymethyl-7,11,15-~trimethyl-
_ _
12-[2-~tetrahydropyran-2-yloxy)] (E)-2,14-hexadecadiene
An excess of the Grignard reagent is added to
a solution of 7-methyl-3-hydroxymethyl-6,7-oxido-8
tosyloxy-(E)-2-octen-1-ol (423.3 mg, 1.3 mmole) in
tetrahydrofuran at 0, followed by Li2CuC14 (0.1 mmole)
and the mixture is stirred for 1.5 hours at 0. The
mixture is allowed to warm to room temperature and then
treated wlth ice water (125 ml) and ethyl acetate
~400 ml). The organic phase is separated, dried
(Na2SO4) and evaporated ln vacuo to give the crude
product. This material is then treated with acetic
anhydride (10 ml) and pyridine (2 ml) and stirred for
16 hours at room temperature. The resulting mixture
is treated with ether (100 ml) and then washed with
saturated cupric sulfate solution (100 ml) and 5%
sodium bicarbonate solution (100 ml). The organic
phase is dried (Na2SO4) and evaporated ln vacuo to give
an oil (210 mg) which is further puri~ied by column
chromatography on silica gel (7 g, 7% ethyl acetate in
hexane) to give 1-acetoxy-3-acetoxymethyl-7,11,15-
trimethyl-12-[2-(tetrahydropyran-2-yloxy)]-(E)-2,14-
hexadecadiene as a colorless oil (41 mg, 9%).
ir (neat) 1735 cm 1; nmr (CDC13)S: 1.23 (s, 3H,
CH3 ~ ~ H , 2.0 and 2.03 ~both s, 6h, CH3-C~
~'7~335~
16
EXAMPLE 14 (Cont'd)
2.66 (bt, J=6 Hz, lH ~ , 5.60 (bt, J=6 Hz~ lH,
\C~C
\CH20Ac ) -
EXAMPLE 15
2S*, 3R*-3-Acetoxy-6E~acetoxyethylidene)-2-methyl-2-
[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenvl]-
_ . .
oxepane and 2S*, 3$*-3-acetoxy6E-(2-acetoxyethylidene)-
2-methyl-2-[4,8-dimethyl-5-(2-tetrahydropyran-2_yloxy)
-7-yloxy 7~nonenyl]-oxepane
A mixture o 1-acetoxy-3-acetoxymethyl-7,11,15-
trimethyl-12-~2-(tetrahydropyran--2-yloxy~]-(E)-2,14-hexadecadiene
(lOmg,0.02 mmole), methanol (5 ml), saturated potassium
carbonate solution (1 ml) and water (1 ml) is stirred at
room temperature for 3 hours. The mixture is then treated
with ethyl acetate (15 ml) and water (15 ml). The
organic phase is dried (Na2SO4) and the solvent is
removed in vacuo to give 3-hydroxymethyl-6,7-oxido-12-
~2-(tetrahydropyran-2-yloxy)]-7,11,15-trimethyl-~E)-
2,14-hexadecadiene-1-ol as a colorless oil. The oil is
dissolved in ether (5 ml)/ treated with boron trifluoride --
etherate (5 drops) and stirred for 90 minutes at room
temperature. The resulting mixture is treated with
pyridine (2 ml) and acetic anhydride ~1 ml) and
stirred for 16 hours. Most of the solvent is evapo~ated
in vacuo and the residue (15 mg) is purified by column
__.
chromatography on silica gel (1 g, 20% ether in
petroleum ether to give a mixture of 2S*, 3R*-3-
` acetoxy-6E~(2-acetoxyethylidene)-2-methyl-2 [4,8-dimethyl-
5-(2-tetrahydropyran-2-yloxy)-7-nonenyl}oxepane and
2S*, 3S*-acetoxy~E-(2-acetoxyethylidene) - 2-methyl-2-
~4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-nonenyl]--
oxepane as a colorless oil (2 mg, 20%). The mixture of
compounds is separated by preparative thin layer
chromatography (silica gel, 30~ ethyl acetate in hexane).
~:~lt7~35;~
17
EXAMPLE 16
2S*, 3R*-3-Acetoxy~E-(2-acetoxyethylidene) ~ 2-methyl-2-
- (4~8-dimethyl-5-hydroxy-7-nonenyl)-oxepane
2S*, 3R*-3-Acetoxy~E-(2-acetoxyethyliden~-2-~ethyl~
2-[4,8-dimethyl-5-(2-tetrahydropyran-2-yloxy)-7-
nonenyl]-oxepane (2mg, 0.02 mmole) in tetrahydrofuran
(2 ml), water (0.3 ml) and glacial acetic acid (2 drops)
is heated at 65 (bath temperature) in a well-capped
test tube for 2 hours. The mixture is allowed to cool
to room temperature and is treated with ether (10 ml)
and water (3 ml). The organic phase is dried (Na2SO~)
and the solvent is removed _ vacuo to yive a colorless
oil (1.5 mg). The oil is homogeneous as determined by
thin layer chromatography analysis (30~ ethyl acetate
lS in hexane).
ir (nea~); 3497, 1739 cm 1; nmr (CDC13)~; o.sn (d,
J=6 Hz, 3H, OEI3-CH), 1.13 (s, 3H, CH3-¢-O-), 1062 and
1.73 [both s, 3H each, (C}I3)2C=CH], 2.03 (s, 6H, CH3CO2),
4.10 (bs, 2H,\O-CH2-C=), 4.60 (d, J=7 Hz, 2H, =C-CH2OAc),
5.32 5m, 2H, /C-CH- and ~=CH-CH2OAc).
EXAMPLE 17
2~,3~6E~2-Hydroxyethylidene)-2-methyl-2t~,8-dimethyl-
5-oxo-7-nonenyl)-oxepan-3-ol
-
A. 2S~,3R~3-Acetoxy~æ-(2-acetoxyethylidene)-
2-me~hyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane
(333 mg) is dissolved in acetone (5 ml) and treated
slowly with Jones reagent (2 mmole) at 0 under nitrogen.
The resulting mixture is stirred for 7 minutes and then
treated with ether (30 ml) and water (20 ml). The
layers are separated and the aqueous layer is extracted
with ether (20 ml). The combined organic layer is
washed with water (30 ml), dried (MgSO4) and evaporated
ln vacuo to give an oil. The crude product is used as
such in the next step.
B. The crude product obtained above (161 mg)
is dissolved in tetrahydrofuran (5 ml) and water (5 ml).
3Si~ `
18
EXAMPLE 17 (Cont'd)
To this mixture, tetra n-butyl ammonium hydroxide
(20~ solution in methanol, 1 ml) is added under nitrogen
at room temperature and the resulting mix~ure is
stirred for 40 hours. The mixture is treated with
ether (S0 ml) and the organic layer is washed with 10~
hydrochloric acid ~2x15 ml), dried (MgSO~) and evaporated
ln vacuo to give an oil. This crude product is purified
by chromatography on a SilicAR column (5 g). 2S*,3R*-
6~~(2-hydroxyethylidene~-2-methyl-2-(4,8-dimethyl-5-
oxo-7-nonenyl)-oxepan-3-ol (81.8 mg) is eluted with
ether. Its ir, nmr spectra, Rf on thin layer and
retention time on gas chromatography are identical to
those o~ the natural product (Compound I~ reported in
U.S. Patent No. 4,086,358. The compound has the
following physical analysis:
ir (neat) p: 2.91 and 5.88
nmr CTDC13 ~: 5-41 (m, 2H, &=CH-CH2OH and
\C=CH-CH2-8-); 4.20 (d, 2H, )C=CH-CH2OH); 4.15 (s, 2EI,
C-O-CH2-C-); 3.58 [broad tjl~, ~CH(OH) ]; 3.18 (d, 2H,
~C=CH-CH2-~-); 1.71 [d, 6H, ~C=C-(CH3)2~; 1.15 (s, 3H,
~C-O- I -CH3 )
Mass spec ~m/e]: 320 [M-18], 251, 233, 221, 171, 143,
141, 137, 125, 113, 97, 95, 81, 69
Chemical Ionization: M+ ~ H = 339; M.W. = 338
~1~93SI~
19
EXAMPLE 18
8-Acetox -2 6-dimeth 1-5-[(1-ethoxYethoxy)]-2-octene
Y ~ Y
A mixture o~ 8-acetoxy-2,6-dimethyl-5-hydroxy-2-
octene~2.27g, 10.6 mmole), ethyl vinylether (0.82 g.
11.4 mmole), ~toluenesulfomc acid monohydrate (catalytic
amount) and ether (50 ml) is stirred a~ room temperature
for 16 hours. The resulting mixture is treated with
ether (150 ml) and washed with 5% sodium bicarbonate
solution (2X100 ml). The organic phase is dried
(Na2SO4), and evaporated in vacuo to give the crude
product. The crude material is further purified by column
chromatography on silica gel (25 g, 5% ethyl acetate in
hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-
2-octene as a colorless oil.
EXAMPLE 19
3,7-Dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol
2 A mixture of 8-acetoxy-2,6-dimethyl-5-~(1-ethoxy-
ethoxy)]~2-octene (0.5mmol~), saturated potassium carbonate
solution (9 ml), water (6 ml) and methanol (100 ml) is
stirred for 3 hours at room temperature. Most of the
methanol is removed in vacuo and the residue is treated
with ethyl acetate (500 ml) and water (200 ml). The
organic phase is dried (Na2SO4) and evaporated in vacuo
to give the crude product. This material is further
purified by column chromatography on silica gel (25 g,
15~ ethyl acetate in hexane) to give 3,7-dimethyl-4-
5 [(1-ethoxyethoxy)]-6-octen-1-Ql as a colorless oil.
EXAMP~E 20
8-Bromo-2,6-dimethyl-5 [(1-ethoxyethoxy)]-2-octene
Triphenylphosphine (1.83g, 7.02 mmole) in methylene
chloride (30 ml) is added to a mixture of 3,7-dimethyl-4-
~ ethoxyethoxy)]-6-octen-1-ol (4.7mmQle) carbon tetra-
3~ ~
bromide (1.94 g, 5~85 mm), pyridine (2 ml) andmethylene chloride at 0C under nitrogen. The resulting
mixture is allowed to warm to room temperature and stirred
for 4 hours after which it is treated with methylene
chloride (lO0 ml) and washed with 5% sodium bicarbonate
solution. The organic phase is dried and evaporated
ln vacuo to give the crude product. This material is further
purified by column chromatography on silica gel (lO0 g, 2
ethyl acetate in hexane) to give 8~bromo-2,6-dimethyl-5-
O [(l-ethoxyethoxy)~-2-octene as a colorless oil.
EXAMPL~ 21
l-Acetoxy-3-acetoxymethyl-7,11,15-trimethyl-12-[(1-ethoxy-
ethox )]-(E)-2,14-hexadecadiene
Y
The Grignard reagent is prepared from 8-bromo-2,6-
15 dimethyl-5-[(l-ethoxyethoxy)]~2-octene(26 mm~le~ and magnesium
(27.1mmole)intetrahydrofuran (35 ml) at room temperature
under argon. An excess o~ the Grignard reagent is
added to a solution of 7-methyl-3-hydroxymethyl-6,7-
oxido-8-tosyloxy-(E)-2-octen-l-ol (423.3 mg, 1.3mmole) in
20 tetrahydrofuran at 0C, followed by Li2CuCl4(0.1mmole) and
the mixture is stirred for 1.5 hours at 0. The mixture
is allowed to warm to room temperature and then treated
with ice water (125 ml) and ethyl acetate (400 ml). The
organic phase is separated, dried (Na2S04) and evaporated
25 in vacuo to give the crude product. This material is then
treated with acetic anhydride (lO ml) and pyridine (2 ml)
and stirred for 16 hr. at room temperature. The resulting
mixture is treated with ether (lO0 ml) and then washed
with saturated cupric sulfate solution (lO0 ml) and 5~
30 sodium bicarbonate solution (lO0 ml). The organic phase is
dried (Na2S04) and evaporated ln vacuo to give an oil which
is further purified by column chromatography on silica yel
~7~35~
(7 g, 7% ethyl asetate in hexane) to give 1-acetoxy-3-
acetoxymethyl-7,11,15-trimethyl~12-[(1-ethoxyethoxy)]
(E)-2,14-hexadecadiene as a colorless oil.
