Total Synthesis of Estradiol Methyl Ether and Its Five-Pot Synthesis with an Organocatalyst

Article abstract of DOI:10.1002/ejoc.201800910

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a highly diastereo- and enantioselective manner. The key reaction is diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives with A, C, and D rings of the steroids as a single isomer with excellent enantioselectivity. Each reaction was optimized, and the total synthesis could be accomplished in 12 pots with 10 purifications using silica gel, resulting in an overall yield of 6.8 %. The reaction sequence and reaction conditions were then optimized in terms of pot economy, whereupon estradiol methyl ether could be synthesized using five reaction vessels with four purifications in an overall yield of 15 %. Notably, six reactions, namely, oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction could be carried out in the last one-pot sequence.

Full text of DOI:10.1002/ejoc.201800910

A Journal of
Accepted Article
Title: Total synthesis of estradiol methyl ether and its five-pot synthesis
through the use of an organocatalyst
Authors: Seitaro Koshino, Eunsang Kwon, and Yujiro Hayashi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800910
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European Journal of Organic Chemistry
10.1002/ejoc.201800910
FULL PAPER
Total synthesis of estradiol methyl ether and its five-pot
synthesis through the use of an organocatalyst
[a]
[b]
[a]
Seitaro Koshino, Eunsang Kwon and Yujiro Hayashi*
Abstract: Enantioselective total synthesis of estradiol methyl ether
has been accomplished in a highly diastereo- and enantioselective
manner. The key reaction is diphenylprolinol silyl ether mediated
domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane
derivatives with A, C, and D rings of the steroids as a single isomer
with excellent enantioselectivity. Each reaction was optimized, and
the total synthesis could be accomplished in 12 pots with 10
purifications using silica gel, resulting in an overall yield of 6.8%. The
reaction sequence and reaction conditions were then optimized in
terms of pot economy, whereupon estradiol methyl ether could be
synthesized using five reaction vessels with four purifications in an
overall yield of 15%. Notably, six reactions, namely, oxidation,
hydrogenation, formation of acid chloride, Friedel–Crafts reaction,
deprotection, and reduction could be carried out in the last one-pot
sequence.
for the synthesis of the Wieland–Miescher ketone, which is a key
[
7]
intermediate of the steroid synthesis.
O
OH
H
H
H
H
H
H
HO
HO
estrone
estradiol
OH
OH
H
OH
H
H
H
H
H
HO
MeO
estriol
estradiol methyl ether (1)
Figure 1. Estrone, estradiol, estriol, and estradiol methyl ether (1)
Recently, Hong reported the one-pot synthesis of a steroid
framework through organocatalyst-mediated Michael/Michael/
aldol/Henry and Michael/Michael/Henry reactions,[ on the other
hands, Jørgensen reported the construction of the steroid
Introduction
8]
Steroids, with a tetracyclic molecular framework, have versatile,
strong, and important biological activities.[1]
Given their
structure by using Torgov’s diene via
a
dienamine
3bu]
importance in medicine and biology, many synthetic methods
have been developed for the efficient synthesis of steroids.[2]
Estrogen is a member of the steroid family and is a female sex
hormone. There are three estrogen compounds that have
estrogenic hormonal activity in females; namely, estrone,
estradiol, and estriol (Figure 1). Given their important biological
intermediate.[
List reported a short synthesis of estrone
through chiral disulfon-imide-mediated Torgov cyclization as a
key step.[
3bv]
On the other hand, our group[9] and Jørgensen’s group[10]
independently developed diphenylprolinol silyl ether 2,[11] and we
reported the asymmetric Michael reaction of nitroalkane and ,-
activities, many total syntheses of these molecules have been
unsaturated aldehyde catalyzed by this catalyst (Eq. 2).[
12]
developed.[
3]
Racemic estrone was synthesized by cobalt-
[
3o]
catalyzed reaction by Vollhardt,
and Torgov reported a short
synthesis of racemic estrone through acid-catalyzed reaction as
a key step.[
3e]
Corey reported an excellent short synthesis of
[
3bj]
[4]
chiral estrone by using CBS reduction.
Organocatalysis has
become
a major category of catalysts, and it has been
successfully employed in the synthesis of steroids. The proline-
mediated intramolecular aldol reaction, reported in 1971 by Hajos
[
5]
and Parrish at Hoffmann-La Roche and by Eder, Sauer,
Wiechert at Schering AG[ independently, is
6]
a
landmark
discovery in organocatalysis (Eq. 1). This approach is effective
[
[
a]
b]
Prof. Dr. Y. Hayashi, S. Koshino,
Department of Chemistry,Graduate School of Science
Tohoku University 6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-
Based on the Hajos–Parrish–Eder–Sauer–Wiechert reaction
and on our own reaction, we expected that the key intermediate
of the estradiol could be synthesized efficiently (Scheme 1): When
nitroalkane 3 was treated with ,-unsaturated aldehyde 4a in the
presence of diphenylprolinol silyl ether 2, Michael reaction would
proceed to provide enamine 5, which would react with the
carbonyl moiety through intramolecular aldol reaction to afford 6a,
possessing A, C, and D rings of the steroid. In this paper, we
describe the realization of the synthesis shown in Scheme 1 and
8578 (Japan)
E-mail:yhayashi@m.tohoku.ac.jpHomepage:
http://www.ykbsc.chem.tohoku.ac.jp
Prof. Dr. E. Kwon
Research and Analytical Center for Giant Molecules,Graduate
Schoolof Science,
Tohoku University 6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-
8578 (Japan)
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European Journal of Organic Chemistry
10.1002/ejoc.201800910
FULL PAPER
the application of the product to the five-pot total synthesis of
estradiol methyl ether (1).[13]
Scheme 1. Synthetic route to estradiol methyl ether (1)
45% yield (Eq. 3). In the case of 3-(1-methylcyclo hexyl)prop-2-
enal no reaction proceeded because of steric hindrance.
Results and Discussion
Table 1. Effect of solvent and water in the domino reaction of 3 and 4b[a]
We first investigated the reaction of nitroalkane
3 with
cinnamaldehyde 4b as model in the presence of
a
diphenylprolinol silyl ether 2. It was necessary to determine (1)
whether the reaction proceeded or not, (2) whether the
diastereoselectivity was high, considering that five contiguous
stereochemical centers would be generated, (3) whether the
enantioselectivity was high, and (4) whether the stereochemistry
accorded with that of steroids.
2
As previous studies indicated that alcohols or THF/H O are
ratio of
:4b
H
2
O
Yield
[%]
suitable solvents for the asymmetric Michael reaction of
ee [%][f]
Entry
Solvent
MeOH
[
d]
[e]
3
addition
nitroalkane,[ we investigated solvents such as MeOH, iPrOH
14]
and THF/H
2
O (Table 1, entries 1, 2, 3) and found that iPrOH was
1[b]
3:1
3:1
yes
no
46
62
69
69
51
58
91
<10
nd
nd
nd
nd
nd
nd
97
nd
suitable. The ratio of nitroalkane 3 and cinnamaldehyde 4b was
then examined, which revealed that an excess of nitroalkane gave
better yield (entries 3, 4, 5, 6). Slow addition of cinnamaldehyde
2[b]
3[b]
4[b]
THF/H
2
O (9:1)
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
3:1
yes
yes
yes
yes
yes
no
4
b dramatically increased the yield, even though only a slight
excess amount of cinnamaldehyde was employed (entry 7).
Moreover, a small amount of water (three equivalents) was
essential for this reaction (entries 7, 8), probably because it
facilitates the hydrolysis of the iminium ion of the intermediate 7
5:1
5[b]
1:1
6[b]
1:1.2
1:1.2
1:1.2
(
Figure 2). Under the best reaction conditions, we were pleased
7[c]
8[c]
to find that the desired bicyclo[4.3.0]nonane derivative 6b was
obtained as a single isomer in excellent enantioselectivity (97%
ee) with the correct stereochemistry of the steroids. Five
contiguous chiral centers were thus completely controlled with the
desired configuration.
The wide generality of the reaction is summarized in Table 2;
for substrates with aryl substituents at the 3-position of propenal,
not only electron-rich p-methoxyphenyl and p-tolyl substituents
but also phenyl groups with electron-deficient p-fluoro, p-chloro,
p-bromo, and o-fluoro substituents are suitable, affording the
bicyclo[4.3.0]nonane derivatives in good yield with excellent
diastereo- and enantioselectivities. In all cases, a single
diastereomer was obtained. Some of the products precipitated
out as solids as the reaction proceeded.
[
a] The reaction was performed by employing nitroalkane (1.0 mmol), ,-
enal, organocatalyst 2 (0.1 mmol), PhCO H (0.2 mmol), additive and solvent
(6.5 mL) at room temperature. [b] All reagents were added from the beginning.
c] 4b were added as slowly. See the supporting information in detail. [d] H
3.0 eq.) was employed as an additive. [e] Isolated yield of purified product.
f] Determined by HPLC analysis on a chiral phase after treatment of the
product with HC(OMe) and p-TsOH. nd = not determined.
2
[
(
[
2
O
3
We then examined the use of ,-unsaturated aldehydes with
a -alkyl substituent. In the reaction of crotonaldehyde 4h, the
diastereoselectivity was low, affording the two isomers in 36% and
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European Journal of Organic Chemistry
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O
corresponds to C6, (2) construction of the B-ring, and (3)
conversion of both NO at C11 and OH at C14 into H (Scheme 2).
2
O2N
H
The order of these transformations was expected to be important.
Our plan was to install the one-carbon unit at C6 first and to make
the B-ring next, during which functional group transformations
would be conducted. One carbon introduction with a formyl moiety
was investigated, but this was found to be troublesome. When
H
OH
N
TMSO
Ph
Ph
7
3 3 2
Wittig reagents such as Ph P=CHOMe or Ph P=CH were treated
Figure 2. The intermediate 7 of the domino Michael/aldol reaction
Table 2. The generality of the domino Michael/aldol reaction[a]
with aldehyde 6a, the desired compound was not obtained, with
only decomposition of 6a being observed, probably because
aldehyde 6a is sterically
Entry
Ar
p-MeOC
Ph
dr
Yield [%][b]
ee [%][c]
>99
97
1
2
3
4
5
6
7
6
H
4
-
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
89
91
86
78
94
85
81
p-tolyl
p-FC
98
6
H
4
-
97
Scheme 2. Synthetic plan of estradiol methyl ether (1) from 6a
p-ClC
6
H
4
-
98
p-BrC
6
H
4
-
98
hindered and is unstable under basic conditions. Gratifyingly,
KCN was found to react with 6a to afford cyanohydrin 7 as a single
isomer, which was treated with thiocarbonyldiimidazole (Im CS)
2
o-FC
6
H
4
-
98
to provide cyclic thiocarbonate 8 in 79% yield over two steps
[
a] Unless otherwise shown, the reaction was performed by employing
nitroalkane (1.0 mmol), -enal (1.2 mmol), organocatalyst 2 (0.1 mmol,
0 mol%), PhCO H (0.2 mmol), water (3.0 mmol) and iPrOH (6.5 mL) at
(Scheme 3). Houben–Hoesch reaction of 8 in the presence of
1
2
[15]
Lewis acid including ZnCl
2
did not generate the B-ring, probably
room temperature. See supporting information for details. [b] Isolated yield
of purified product. [c] Determined by HPLC analysis on a chiral phase after
treatment of the product with HC(OMe)
because of the unsuitable configuration, in which cyano and aryl
moieties are separated (Figure 3).
3
and p-TsOH. See supporting
information for details.
Instead of the cyclic thiocarbonate 8, we tried to protect the
diol with bis methyl xanthate (Scheme 4). When aldehyde 6a was
2
treated with KCN, then CS and MeI at -20 °C, mono methyl
xanthate 9 was obtained without the formation of the bis- xanthate.
Without purification of 9, dehydrated alkene 10 was obtained in
2
90% yield by the treatment of 9 with SOCl and pyridine. The
relative and absolute stereochemistries were confirmed by the X-
ray crystallographic analysis (Figure 4)[16]. Reductive removal of
xanthate 10 using nBu
3
SnH and AIBN under Barton– McCombie
conditions[17] was carried out at 80 °C
Given that we obtained 6a with excellent enantioselectivity in
a single operation (Table 2, entry 1), the rest of the major
transformations for the synthesis of estradiol methyl ether (1)
involved the following: (1) introduction of a one-carbon unit, which
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European Journal of Organic Chemistry
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O
O
Scheme 3. B-ring construction with cyclic thiocarbonate 8
O2N
2
O N
KCN aq. (10.0 eq.)
H
H
H
OH
O
MeCN
25 ˚C, 40 min
H
OH
OH
-
MeO
MeO
NC
6a
7
O
Im2CS (1.5 eq.)
DMAP (0.3 eq.)
O2N
ZnCl2 (3.0eq.)
HCl in dioxane
H
no reaction
DMF, r.t., 1 h
H
O
O
80 ˚C
S
MeO
NC
Figure 3. The configuration of thiocarbonate 8
8
79% (2 steps)
Scheme 4. Synthetic study to construct B-ring of estradiol methyl ether (1)
the C14–15 double bond first; that is, before B-ring formation.
When 12 was treated with Pd/C under H atmosphere, undesired
2
diastereomer 13 was obtained as a single isomer without
formation of the desired isomer 14, because of steric crowding on
the -face (Eq. 4).
We thought that the stereoselective hydrogenation from the
-face would be possible based on Abad’s precedent. [ That is,
the stereoselective reduction of ketone 12 by the appropriate
reductant would provide -alcohol 15, which would be protected
with a bulky protecting group (Scheme 5). Then, the hydrogen-
ation would proceed from the -face because the -face is
shielded effectively. Based on this idea, we investigated the
19]
Figure 4. ORTEP of 10. Thermal ellipsoids are set at the 50% probability.
to provide alkane 11 in good yield (78%). We then examined the
into H using the same reagents,[18] but this was
conversion of NO
2
found to be troublesome. Higher temperature was found to be the
key for the success of this reaction. The reaction at 140 °C using
anisole as a reaction media for 30 minutes gave low yield.
However, when the reaction was carried out at 250 °C for 5
minutes using biphenyl as a reaction media, a better yield was
3
stereoselective reduction first, which proceeded using LiBHEt to
afford -alcohol 15 as a single isomer. Alcohol 15 was protected
with the bulky TIPS group to afford silyl ether 16 in 81% yield over
two steps. Given that the conversion of the cyanide moiety into
carboxylic acid by hydrolysis under both acidic and basic
conditions was unsuccessful, we employed two-step procedures
such as a reduction with DIBAL, followed by the Kraus–Pinnick
oxidation[ to afford 18 in good yield. Hydrogenation of the latter
proceeded with high diastereoselectivity, as expected from the -
face, to provide 19 with the desired stereochemistry at C14.
Intramolecular Friedel–Crafts acylation proceeded by the
achieved (57%).
Although 12 was treated with several Lewis acids, the B-ring
did not form, and byproducts were obtained, which were thought
be generated by the reaction of the activated cyano moiety with
the C14–15 double bond. This result prompted us to reduce
20]
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Scheme 5. Synthesis of estradiol methyl ether (1) from 12 in a seven-pot sequence
treatment of AlCl
deprotection of the silyl ether to provide 20 in 80% yield.
Hydrogenolysis using Pd(OH) in AcOH gave estradiol methyl
3
, and quenching the reaction with HCl led to
(Scheme 6, 3+4a  10). The yield of a single pot (78%) is nearly
same as that of three pots (80%, 0.89  0.90 = 0.80). In this first
pot, the generated product possesses all carbons necessary for
estradiol. It should be noted that five reactions proceeded
sequentially in the same reaction vessel; namely, (1) asymmetric
Michael reaction, (2) intramolecular diastereo-selective aldol
reaction, (3) diastereoselective cyanohydrin formation, (4)
2
ether (1) in 50% yield. We thus accomplished the total synthesis
of estradiol methyl ether (1) in a 12-pot sequence with 10
purifications using silica gel with total yield of 6.8%.
[
21]
Recently, we proposed the term “pot economy”,
because
one-pot operations are an effective method both for carrying out
several transformations and for forming several bonds in a single
pot while at the same time eliminating several purification steps,
minimizing chemical waste generation, and saving time. Based
on this concept, we have reported a 60 min, one-pot synthesis of
xanthate formation, and (5) dehydration reaction.
The next reactions were deoxygenation[17] and radical
denitration[ using the same reagents, nBu
18]
SnH and AIBN. In
3
[22]
[23]
the previous two-pot process (Scheme 4), the first Barton–
McCombie reaction proceeded at 80 °C in 78% yield, and after
purification, the second denitration proceeded at 250 °C in 57%
yield. When the reaction was conducted first at 80 °C then at
(
–)-Oseltamivir,
one-pot syntheses of ABT-341
Baclofen, and three-pot synthesis of PGE methyl ester (Figure
Based on this concept, we began to investigate the
and (S)-
[
24]
1
[
25]
5
).
synthesis of estradiol methyl ether (1) in as few pots as possible.
250 °C in the same pot, the yield dropped to less than 30%. As
the byproducts in the first reaction would affect the second
reaction, the reaction was conducted at 250 °C from the beginning
with the 34% yield of the product. The yield improved to 59%,
when the reaction was carried out under microwave irradiation,
probably because of the immediate efficient heating. Compared
with the two-pot procedure (44%), a higher yield (59%) was
obtained in the single-pot process (Scheme 6, 10  12).
The next reactions were reduction of C17 ketone and
protection of the resulting hydroxy group, and half reduction of
cyano moiety to aldehyde (12  17). There are two reductions in
this scheme, which we tried to combine with a change in the
reaction order. Although DIBAL can reduce ketone and cyano
moiety at the same time, the diastereoselectivity in the reduction
Figure 5. The examples of pot economical total synthesis by our group
3
of ketone is poor (dr = 2:1). Thus, LiBHEt , which can reduce the
ketone with high diastereoselectivity, should be employed in the
first reduction, but it cannot reduce the cyano moiety. Then, two
reductions were conducted in a single pot, in which the amounts
of the reductants were found to be crucial for the success of this
one-pot reaction. When 12 was treated with 1.2 equiv. of LiBHEt ,
3
followed by DIBAL (2.0 equiv.), aldehyde 21 was afforded. After
The solvent in the first domino reaction of asymmetric Michael
reaction and intramolecular aldol reaction is iPrOH, which is not a
good solvent in the second cyanohydrin formation. The solvent
in the second reaction is MeCN, which is not suitable for the third
reaction. Thus, after the first and the second reactions, solvent
swaps were performed. After each reaction, the solvents were
removed under reduced pressure, and the replacement solvent
was added. By using this procedure, the previous three-pot
operations can be carried out in a single pot, and good yield and
excellent diastereo- and enantioselectivities were maintained
quenching, the latter was silylated without purification to provide
1
7 in 47% yield via two pots from 12, in which amine 22 was
observed by the overreduction of generated imine with remaining
LiBHEt (Figure 6). This overreduction was not observed in the
separate pot reaction. By using exactly one
3
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Scheme 6. Four pot transformation from 3 and 4a to 17
Scheme 7. One-pot synthesis of estradiol methyl ether (1) from 17
reduced pressure, and CH
2
Cl
2
was added. Carboxylic acid 19
was then converted into acid chloride 23 by treatment with oxalyl
chloride as a third reaction. The fourth reaction was the Friedel–
Crafts acylation, which proceeded well by the addition of AlCl
The addition of methanol, which reacts with AlCl to generate HCl,
cleaves silyl ether to generate alcohol 20 as a fifth reaction. After
removal of the solvent, hydrogenolysis using Pd(OH) in AcOH
3
.
3
Figure 6. Byproduct of one-pot reduction of 12
2
gave estradiol methyl ether (1) as a sixth reaction. It should be
noted that the metal-catalyzed hydrogenolysis reaction
proceeded well even after five reactions in the presence of many
3
equivalent of LiBHEt , followed by DIBAL reduction, this problem
can be addressed to afford the desired product 17 in two pots after
silylation, in 59% yield (Scheme 6, 12  17).
The last pot process combines six steps (Scheme 7). The first
reaction was Kraus–Pinnick oxidation[20] of aldehyde 17 to
byproducts and side products.
Regarding formation of the B-ring, it should be mentioned that
although the B-ring in 24 was constructed by the intramolecular
Friedel–Crafts acylation from acyl chloride 23, the
carboxylic acid 18, and the second reaction was the
hydrogenation. When these two reactions were conducted in the
same pot sequentially, the second reaction did not proceed at all,
probably because the remaining oxidant would act as a catalyst
poison. To reduce the remaining oxidant, we added acetaldehyde
after the first reaction, expecting that it would not only reduce the
oxidant but also generate acetic acid, which would accelerate the
hydrogenation. As expected, by the addition of acetaldehyde
after the first reaction, the second reaction also proceeded
smoothly. After the second reaction, solvent was removed under
other regioisomer, 26, was selectively formed by the intra-
molecular Houben-Hoesch reaction from the cyanide derivative
[16]
25 in 51% yield (Eq. 5). The latter would be generated by the
ipso-addition of the p-methoxybenzene moiety on the activated
cyanide, followed by dienone-phenol rearrangement. The subtle
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European Journal of Organic Chemistry
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difference of the substrates changed the reaction path, and 2-
methoxy 3-dehydroxy estradiol isomer would be synthesized from
this intermediate.
was quenched with phosphate buffer (pH = 7.0, 3.0 ml). The reaction
mixture was extracted with EtOAc (5.0 ml) three times, then the organic
layers were washed by brine (10 ml), dried over Na SO , and concentrated
2 4
in vacuo after filtration. After preparative TLC purification of crude
materials, the product Acetal-6 was obtained.
Conclusions
(
2S)-2-((3aS,4R,5S,6R,7aS)-3a-hydroxy-5-(4-methoxyphenyl)-7a-
methyl-6-nitro-1-oxooctahydro-1H-indene)-2-hydroxyacetonitrile
thiocarbonate (8): To a solution of 6a (2470 mg, 7.11 mmol) in MeCN
The enantioselective total synthesis of estradiol methyl ether (1)
has been accomplished in
a
highly diastereo- and
(
47.4 ml) was added KCN aq. (10 ml, 7.1 M, 71.1 mmol) at -20 ˚C. After
stirring the reaction mixture for 40min, to the reacting mixture was added
sat. NH Cl aq. (50 ml, 0 ˚C) and the organic layers were washed with
NH Cl aq. and dried over Na SO . Following filtration and concentration,
400 mg of crude material was obtained. Then the crude material was
dissolved into 14.2 ml of DMF. To the solution were added CS Im (1900
enantioselective manner. One of the key reactions is a domino
reaction of diphenylprolinol silyl ether-mediated Michael reaction
of nitroalkane 3 and intramolecular aldol reaction to afford
bicyclo[4.3.0]nonane derivatives with A, C, and D rings of the
steroids as a single isomer with excellent enantioselectivity. Five
contiguous chiral centers are completely controlled with the
desired configuration. This key reaction has a wide generality.
Given that the domino product possesses several functional
groups such as nitro and hydroxyl groups at suitable positions, it
constitutes a useful synthetic intermediate for the synthesis of
steroid derivatives. Stereoselective hydrogenation of 18 was
realized by shielding the bulky siloxy protecting group at the -
face. Total synthesis can be accomplished in 12 pots with 10
purifications using silica gel with total yield of 6.8%. After the
completion of the synthesis, the reaction sequence and reaction
conditions were optimized again in terms of the pot economy. As
4
4
2
4
2
2
mg, 10.66 mmol) and DMAP (260 mg, 2.13 mmol), and the solution was
stirred for 40 min. To the resulting reaction mixture was added 60 ml of
2
H O and the precipitate was collected by filtration. After drying in vacuo,
analytical pure 8 (2256 mg) was obtained.; ¹H NMR (400 MHz, CDCl ) δ
3
1.18 (3H, s), 2.00 (1H, dd, J = 14.8, 3.6 Hz), 2.21-2.44 (7H, m), 2.73 (1H,
dd, J = 8.8, 8.8 Hz), 3.10 (1H, ddd, J = 14.4, 14.4, 19.6 Hz), 3.32 (1H, dd,
J = 12.4 ,12.4 Hz), 3.61 (1H, dd, J = 12.4, 6.8 Hz), 3.66 (3H, s), 5.05( 1H,
ddd, J = 12.0, 12.0, 3.6 Hz), 5.34(1H, d, J = 6.8 Hz), aromatic proton is
strongly broadening, which could not be assigned.
O-((S)-cyano((4R,5S,6R,7aS)-5-(4-methoxyphenyl)-7a-methyl-6-nitro-
1
-oxo-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)methyl)
carbonothioate (10): To a solution of 6a (1494 mg, 4.3 mmol) and CS
1.30 ml, 21.5 mmol) in 29 ml of MeCN was added KCN aq. (6.32 ml, 6.9
O-methyl
2
3
a result, two reductions (LiBHEt and DIBAL) could be conducted
(
in the same pot. Six reactions—namely, oxidation, hydrogenation,
and formation of acid chloride, Friedel–Crafts reaction,
deprotection, and reduction—can be carried out in the last one-
M, 43 mmol) at – 18 ˚C and the reaction mixture was stirred for 10 min.
Then MeI (1.338 ml, 21.5 mmol) was added and the reaction mixture was
stirred for 30 min at the temperature. Then, to the reaction mixture was
added sat. NH
by AcOEt (20 ml, 3 times). The organic layer was washed by sat. NH
aq (20 ml), and brine (20 ml, 2 times). After drying by Na SO and filtration
of it, 2000 mg of crude materials were obtained. Then the crude materials
were dissolved with pyridine (28.6 ml). To the solution was added SOCl
1.40 ml, 19.35 mmol) at 0 ˚C, and the reaction mixture was stirred for 30
4
Cl aq. (30 ml), and the organic components were extracted
pot sequence.
Thus, estradiol methyl ether (1) can be
4
Cl
synthesized using five reaction vessels with four purifications with
total yield of 15%. By the use of pot methodology, (1) the number
of pots is reduced from 12 to 5, (2) the number of purifications is
reduced from 10 to 4, (3) the total yield is increased from 6.8% to
2
4
2
(
1
5%, and (4) the total time including the reaction, quenching, and
min. Then, to the reaction mixture was added 70 ml of 1N HCl aq. and
organic components were extracted by AcOEt (20 ml, 3 times). The
purification can be reduced.
organic layer was washed by sat. NH
times). After drying by Na SO and filtration, analytical pure 10 (1790 mg)
was obtained as yellow solid.; mp = 205-206 ˚C; [훼]퐷 = +66.44 (c 1.00,
CHCl ); Rf = 0.35 (hexane-EtOAc = 2:1); ¹H NMR (400 MHz, CDCl ) δ
.33 (3H, s), 2.00 - 2.07 (2H, m), 2.44 (1H, dd, J = 12.8, 4.0 Hz), 2.58 (3H,
s), 3.09 - 3.28 (4H, m), 3.81 (3H, s), 5.05 (1H, ddd, J = 11.2, 11.2, 4.0 Hz),
.95 (1H, d, J = 3.6 Hz), 6.25 (1H, dd, J = 2.0, 2.0 Hz), 6.92 (2H, d, J = 8.8
Hz), 7.20 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CDCl
) δ 19.9, 20.6,
7.1, 41.5, 42.4, 49.5, 50.3, 55.3, 67.5, 87.7, 113.6, 115.0 (2C), 120.8,
25.7, 128.9 (2C), 140.0, 160.1, 213.3, 215.8; IR (neat) ν(cm ) : 3457,
273, 1746, 1613, 1556, 1514, 1459, 1372, 1255, 1182, 1069, 835, 753;
Any identical peak of 10 could not be observed in the HRMS (ESI). (10
would be unstable in the ESI MS analysis)
4
Cl aq. (20 ml), and brine (20 ml, 2
2
4
26
Experimental Section
3
3
1
Synthesis of (3aS,4R,5S,6R,7aS)-3a-hydroxy-7a-methyl-6-nitro-1-
oxo-5-aryloctahydro-1H-indene-4-carbaldehyde
procedure for domino Michael/aldol reaction): The solution of
nitrodiketone 3 (0.83 mmol) in 1.3 ml of iPrOH, PhCOOH (0.17 mmol),
catalyst 2 (0.08 mmol) and H
temperature for 5 minutes. Then the solution of -aldehyde 4 (1.0 mmol)
in iPrOH (5.3 ml) was slowly dropped into the reaction mixture over 10 h
by syringe pump. After stirring it for additional 1 h, the reaction mixture was
concentrated in vacuo at 40 ℃ for 1 h. The crude material was purified by
silica gel column chromatography (EtOAc : hexane = 1:2). The product 6
was obtained. Enantiomeric excess was determined by HPLC analysis
after conversion of 6 to Acetal-6 by acetalization.
(6)
(general
5
3
3
1
2
2
O (2.4 mmol) was stirred at room
-1
2
-((4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-oxo-2,4,5,6,7,7a-
hexahydro-1H-inden-4-yl)acetonitrile (12): The benzene solution (40
ml) of 10 (1790 mg, 4.0 mmol), nBu SnH (4.31 ml, 16 mmol) and AIBN
525 mg, (3.2 mmol) was stirred for 2 h at 80 ˚C. After cooling to room
3
(
(
3aS,4R,5S,6R,7aS)-4-(dimethoxymethyl)-3a-hydroxy-7a-methyl-6-
temperature, the resulting solution was concentrated in vacuo. Then the
crude materials were washed with MeCN / hexane solutions to remove
excess Sn wastes. The MeCN layers were gathered and concentrated in
vacuo. After column chromatography (Hexane : AcOEt = 2 :1), 1061 mg of
crude 11 was obtained. Crude 11 was mixed with biphenyl (18.5 g, 120
nitro-5-aryloctahydro-1H-inden-1-one (Acetal-6) (General procedure
for acetalization): To a solution of bicyclo[4.3.0]nonane 6 (0.7 mmol) in
CH
mixture was cooled to 0 ℃ and HC(OMe)
stirring the reaction mixture for 30 min at this temperature, and the reaction
2
Cl
2
(700 l), p-TsOH (0.07 mmol) was added at room temperature. The
3
(3.5 mmol) was added. After
3
mmol), nBu SnH (7.8 ml, 29.0 mmol), AIBN (476 mg, 2.90 mmol). The
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European Journal of Organic Chemistry
10.1002/ejoc.201800910
FULL PAPER
mixtures were heated to 80˚C to melt biphenyl and made homogeneous
solution. Then the solution was heated at 250 ˚C by pre-heated oil bath for
2.44 - 2.50 (1H, m), 2.80 - 2.90 (1H, m), 3.79 (3H, s), 4.16 (1H, t, J = 8.0
Hz), 6.85 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 9.49 (1H, dd, J =
5
min. After the completion of reaction, the pressure of the reaction system
2.8, 1.6 Hz); 13C NMR (100 MHz, CDCl
31.3, 37.7, 38.6, 39.5, 44.1, 48.1, 38.9, 54.8, 83.1, 113.7 (2C), 117.2,
128.0 (2C), 136.0, 149.7, 157.9, 202.1; IR (neat) ν(cm ) : 3440, 2940,
3
) δ 11.9, 16.1, 17.7, 17.7, 17.8,
was reduced to 0.1 mmHg and kept at 80 ˚C for 3 h to remove biphenyl.
Then the lasting materials at the flask were washed with MeCN / hexane
solutions to remove excess Sn wastes. The MeCN layer was gathered and
concentrated in vacuo. After column chromatography (Hexane : AcOEt =
-
1
1725, 1612, 1512, 1463, 1248, 1178, 882, 828, 681; HRMS (ESI): [M+Na]+
calculated for C
H
NaO Si: 479.2957, found: 479.2963.
28
44
3
26
2
0
1
=
2
:1), 334 mg of 12 was obtained.; [훼]퐷 = +255.10 (c 1.00, CHCl
3
); Rf =
.25 (hexane-EtOAc = 3:1); ¹H NMR (400 MHz, CDCl ) δ 1.28 (3H, s),
3
2
(
-((1S,4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-
(triisopropylsilyl)oxy)-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)acetic
acid (18): To a solution of 17 (60 mg, 0.131 mmol), NaH PO •H O (63 mg,
.526 mmol) and 2-methyl-2-butene (0.278 ml, 2.63 mmol) in tBuOH (1.5
.44 (1H, ddd, J = 13.2, 13.2, 4.0 Hz), 1.82 - 2.02 (3H, m), 2.25 (1H, dd, J
16.8, 7.6), 2.38 (1H, ddd, J = 12.0 ,12.0, 4.0 Hz), 2.44 (1H, dd, J = 16.8,
.8 Hz), 2.66 - 2.71 (1H, m), 3.00 (1H, ddd, J = 23.2, 2.0, 2.0 Hz), 3.13 (1H,
2
4
2
0
ddd, J = 23.2, 3.6, 1.6 Hz), 3.81 (3H, s), 5.86 (1H, dd, J = 4.4, 2.4 Hz), 6.89
2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl
δ 17.2, 19.3, 29.7, 32.2, 38.9, 41.0, 49.0, 50.8, 54.8, 113.9 (2C), 115.7,
ml) and H
purity, 0.263 mmol, in H
2
O (0.375 ml) was added the solution of NaOCl
2
(30 mg, 70%
(
3
)
2
O 1.5 ml) at 0 ˚C. After stirring for 1 h, reaction
was quenched by adding 5 mL of brine. The organic components were
extracted by AcOEt (5 ml, 2 times). The organic layer was washed with
brine (10 ml), dried over Na
residue was purified by column chromatography (Hexane / AcOEt = 2 :1)
afforded 62 mg of 18.; ¹H NMR (400 MHz, CDCl ) δ1.00-1.18 (24H, m),
-
1
117.8, 127.7 (2C), 134.0, 147.6, 158.2, 219.6; IR (neat) ν(cm ) : 2932,
2244, 1740, 1611, 1513, 1251, 1179, 1034, 830, 506; HRMS (ESI):
2 4
SO , filtrated and concentrated in vacuo. The
[M+Na]+ calculated for C
H
NNaO : 318.1470, found: 318.1483.
19
21
2
3
2
1
-((3aR,4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-oxooctahydro-
H-inden-4-yl)acetonitrile (13): To the solution of 12 (116 mg, 0.40
1.25- 1.40 (2H, m), 1.73 (1H, dd, J = 14.0, 3.6 Hz), 1.81- 2.00 (2H, m),
2.20-2.30 (4H, m), 2.46 (1H, ddd, J = 14.8, 7.2, 2.8 Hz), 2.79 (1H, br), 3.77
(3H, s), 4.15 (1H, dd, J = 8.4, 8.4 Hz), 5.16 (1H, s), 6.83 (2H, d, J = 8.8
Hz), 7.12 (2H, d, J = 8.8 Hz).
mmol) in 2.0 ml of AcOEt was added 10% Pd/C (116 mg, 10 wt%) and the
resulting solution was stirred under H atmosphere (1 atm) for 20 h at room
temperature. After filtration through celite to remove Pd and concentration,
03 mg of pure 13 was obtained.; ¹H NMR (400 MHz, CDCl ) δ1.22 (3H,
2
1
3
2
-((1S,3aS,4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-
(triisopropylsilyl)oxy)octahydro-1H-inden-4-yl)acetic acid (19): To a
solution of 18 (189 mg, 0.40 mmol) in 8 ml of MeOH was added 227 mg of
Pd(OH) (10 wt%) and the solution was stirred under H atmosphere (5
atm) for 14 h at room temperature. After the reaction, Pd(OH) was
s), 1.26 (1H, ddd, J = 14.0, 2.68, 2.8 Hz), 1.48 (1H, ddd, J = 13.2, 13.2, 4.8
Hz), 1.60-1.78 (2H, m), 1.84-2.10 (3H, m), 2.14-2.37 (4H, m), 2.45 (1H,
ddd, J = 12.0, 12.0, 4.4 Hz), 2.56 (1H, dd, J = 18.0, 7.6 Hz), 3.77 (3H, s),
(
2
2
6.84 (2H, d, J= 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz).
2
removed by filtration through celite and the resulting solution was
concentrated. The crude material after concentration was purified by
column chromatography (Hexane / AcOEt = 5 :1, 1% AcOH). 129 mg of 19
2
-((1S,4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-
(
(triisopropylsilyl)oxy)-2,4,5,6,7,7a-hexahydro-1H-inden-4-
yl)acetonitrile (16): To the solution of 12 (350 mg, 1.185 mmol) in 2.37 ml
of THF was added LiBHEt (1.367 ml, 1.0 M) at -78 ˚C. After stirring it for
h, the reaction was quenched by adding 25 ml of 1N HCl aq. After
extraction by AcOEt (5 ml, 3 times), the organic layer was washed by brine
10 mL), dried over Na SO , filtrated and concentrated in vacuo, 440 mg
3
was obtained.; ¹H NMR (400 MHz, CDCl ) δ0.920 (3H, s), 1.00-1.16 (22H,
3
m), 1.15-1.32 (3H, m), 1.41-1.75 (9H, m), 1.85 (1H, dd, J = 12.4 , 2.8 Hz),
1.90-2.10 (2H, m), 2.12-2.30 (3H, m), 3.50 (1H, dd, J = 10.0 ,12.0 Hz), 3.76
(3H, s), 6.82 (2H, d, J = 8.4 Hz), 7.12 (1H, d, J = 8.4 Hz).
3
(
2
4
of crude material containing 15 was obtained. To the solution of the crude
material in 7.9 ml of DMF was added 0.797 ml of TIPSOTf (2.963 mmol)
and 404 mg of Imidazole (5.93 mmol) at 60 ˚C. After stirring it for 12 h,
reaction was quenched by brine and MeOH and the organic materials were
extracted by AcOEt (10 ml, 3 times). The organic layer was washed by
(
8R,9S,13S,14S,17S)-17-hydroxy-3-methoxy-13-methyl-
7
6
,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-
-one (20): To a solution of 19 (42 mg, 0.0875 mmol) in 3.5 ml of CH Cl
(15l, 0.175 mmol) and stirred it for 2.5 h at room
temperature. Then, AlCl (23.3 mg, 0.175 mmol) was added and reaction
mixture was stirred for additional 30 min. After quenching with sat.
NaHCO aq. (5 ml) and filtration, the organic components were extracted
by AcOEt (5 ml, 2 times). The organic layer was washed with brine (10 ml),
dried over Na SO , filtrated and concentrated in vacuo. The crude material
was purified by column chromatography (Hexane / AcOEt = 2 :1) to afford
1 mg of 20.; ¹H NMR (400 MHz, CDCl ) δ0.79 (3H, s), 1.32-1.40 (3H,
m), 1.45-1.57 (1H, m), 1.62 (1H, dd, J = 8.0, 4.0 Hz), 1.63-1.72 (1H, m),
2
2
was added (COCl)
2
3
brine (10ml, 2 times), dried over Na
2 4
SO , filtrated, and concentrated in
vacuo. After purification by column chromatography (Hexane / AcOEt =
3
1
1
2
3
0 : 1), 436 mg of 16 was obtained.; ¹H NMR (400 MHz, CDCl ) δ1.00-
.17 (24H, m), 1.39 (1H, ddd, J = 12.8, 12.8, 4.0 Hz), 1.77- 2.00 (3H, m),
.13 (1H, dd, J =16.8, 6.0 Hz), 2.26-2.30 (1H, m), 2.38-2.28 (2H, m), 2.52
2
4
(
=
1H, br), 2.56 (1H, ddd, J = 15.2, 8.0, 3.2 Hz), 3.80 (3H, s), 4.21 (1H, dd, J
8.0, 8.0 Hz), 5.35 (1H, s), 6.88 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J =8.8
Hz).
2
3
1
2
.90-2.07 (2H, m), 2.10-2.21 (2H, m),2.40 (1H, ddd, J = 14.4, 7.2, 2.8 Hz),
.75 (1H, dd, J = 17.2, 3.6 Hz), 3.76 (1H, dd, J = 14.8, 8.8 Hz), 3.85 (3H,
2
-((1S,4R,5S,7aS)-5-(4-methoxyphenyl)-7a-methyl-1-
s), 7.11 (1H, dd, J = 8.4, 2.8 Hz), 7.35 (1H, dd, J = 8.8, 1.2 Hz), 7.56 (1H,
d, J = 2.8 Hz).
((triisopropylsilyl)oxy)-2,4,5,6,7,7a-hexahydro-1H-inden-4-
yl)acetaldehyde (17): To the solution of 16 (355 mg, 0.733 mmol) in 2.44
2 2
ml of CH Cl was added DIBAL (1.1 ml, 1.0M in hexane) at 0 ˚C. After
estradiol methyl ether (1): To a solution of 20 (12 mg, 0.04 mmol) in 0.8
stirring it for 4 h, reaction was quenched by 5 ml of 1N HCl aq. After stirring
it for additional 4h, organic components were extracted by AcOEt (5 ml, 2
times). The organic layer was washed with brine (10 ml), dried over
ml of AcOH was added 12 mg of Pd(OH)
2
and stirred under H
2
atmosphere
(1 atm) for 12 h. Then, after removing Pd(OH)
2
by filtration through
celite and concentration, the crude material was purified by column
chromatography (Hexane / AcOEt = 2:1) to afford 10 mg of estradiol methyl
2 4
Na SO , filtrated and concentrated in vacuo. After purification of the crude
materials by column chromatography (Hexane / AcOEt = 10 : 1), 29 mg of
26
ether (1).; [훼]퐷 = +69.88 (c 0.40, CHCl
3
); Rf = 0.32 (hexane-EtOAc = 2:1);
) δ 0.78 (3H, s), 1.16~1.54 (9H, m), 1.66~1.74
1H, m), 1.85~1.91 (1H, m), 1.94 (1H,ddd, J = 12.4, 3.2, 3.2 Hz), 2.08~
2
6
1
7 was obtained.; [훼] = +30.74 (c 1.00, CHCl
3
); Rf = 0.45 (hexane-
) δ 1.05 - 1.18 (21H, m), 1.13
3H, s), 1.37 (1H, ddd, J = 12.8, 12.8, 4.0 Hz), 1.75 - 1.81 (1H, m), 1.87 -
퐷
¹H NMR (400 MHz, CDCl
3
EtOAc = 10:1); ¹H NMR (400 MHz, CDCl
3
(
(
2
3
.22 (2H, m), 2.29~2.35 (1H, m), 2.82, 2.88 (2H, m), 3.73 (1H, t, J = 8.4Hz),
.78 (3H, s), 6.63 (1H, d, J = 2.8 Hz), 6.71 (1H, dd, J = 8.4, 2.8 Hz), 7.21
2.01 (2H, m), 2.20 - 2.29 (3H, m), 2.36 (1H, ddd, J = 16.8, 8.4, 2.8 Hz),
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European Journal of Organic Chemistry
10.1002/ejoc.201800910
FULL PAPER
(
1H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl
3
) δ 11.0, 23.1, 26.3, 27.2,
added to the reaction mixture to quench the oxidant and the solution was
2
1
1
2
9.8, 30.6, 36.7, 38.8, 43.2, 43.9, 50.0, 55.2, 81.9, 111.4, 113.8, 126.3,
32.6, 138.0, 157.4; IR (neat) ν(cm ) : 3399, 2925, 1609, 1500, 1465,
stirred for another 30 min. Then, AcOH (3.7 mL) and Pd(OH)
100 mg, 12 wt% as pure Pd(OH) for substrate) were added to the reaction
mixture. The reaction mixture was stirred under H atmosphere (5 atm) at
room temperature for 17 h. The resulting solution was concentrated in
vacuo to remove AcOH and water completely. CH Cl (7.36 ml) and
COCl) (158 l, 1.84mmol) were added to the residue, and stirring the
reaction mixture for 3 h at room temperature, then, AlCl (49.0 mg, 0.368
2
(10 wt%,
-
1
2
254, 1054, 732, 405; HRMS (ESI): [M+Na]+ calculated for C
87.2011, found: 287.2013.
H
O :
2
19
27
2
2
2
(
2
5
Pot synthesis of estradiol methyl ether (1):
3
mmol) was added to the reaction mixture. The color of reaction mixture
changed to red and the reaction mixture was stirred for 1 h. The reaction
was quenched by addition of MeOH (5.5 ml) and the solvent was removed
1
st pot: To a solution of nitroalkane 3 (55.8 mg, 0.30 mmol), catalyst 2
(
0
(
9.8 mg, 0.03 mmol), benzoic acid (6.7 mg, 0.06 mmol) and water (16.2 l,
.90 mmol) in iPrOH (480 l), the solution of -unsaturated aldehyde 4a
59.0 mg, 0.36 mmol) in iPrOH (1.92 ml) was added slowly over 10 h by
in vacuo. AcOH (7.36ml) and Pd(OH)
Pd(OH) for substrate) was added to the resulted mixture and the reaction
mixture was stirred under H atmosphere (5 atm) at room temperature for
2 h. After the completion of the reaction, the mixture was concentrated
after filtration. The residue was purified by column chromatography
hexane-EtOAc = 2:1) to afford estradiol methyl ether (1) (29.0 mg, 0.10
2
(10 wt%, 100 mg, 12 wt% as pure
2
the syringe pump. After stirring the reaction mixture for additional 1 h, the
resulting solution was concentrated in vacuo (40 ˚C, 1 h). After the crude
material was dissolved in MeCN (2.0 ml), CS (90.8 l, 1.50 mmol) was
added to the solution. Then aq. KCN (88.2 l, 0.33 g/ml, 0.60 mmol) was
added to the solution at -20 ˚C and the solution was stirred for 10 min.
Then, MeI (93.2 l, 1.50 mmol) was added to the reaction mixture. After
stirring it for 30 min at -20 ˚C, the resulted reaction mixture was
concentrated in vacuo. The crude material was dissolved in pyridine (2.0
2
1
2
(
mmol, 55% yield) as colorless oil.
ml) and the solution was cooled to 0 ˚C. SOCl
added to the solution and the color turned to dark blown. After stirring it for
0 min, the reaction mixture was quenched by 1 N aq. HCl (4.0 ml) and
extracted with EtOAc (5.0 ml) twice. The organic layer was washed with
brine (5.0 ml) twice, dried over Na SO and concentrated in vacuo after
filtration. The crude material was purified by column chromatography
hexane-EtOAc = 2:1) to give 10 (105 mg, 0.235 mmol) in 78% yield as
2
(135.2 l, 1.35 mmol) was
Acknowledgements
3
This work was supported by JSPS KAKENHI Grant Number
JP16H01128 and JP18H04380 in Middle Molecular Strategy. The
authors thank Ms. Kanna Ojima for her experimental assistance.
2
4
(
blown solid.
Keywords: organocatalysis • total synthesis • steroids • Pot-
Economy • domino reactions
2nd pot: Compound 10 (268 mg, 0.60 mmol), AIBN (78.8 mg, 0.48 mmol)
3
and nBu SnH (1.29 ml, 4.8 mmol) were dissolved in anisole (2.0 ml), and
[
[
1] J.-F. Biellmann, Chem. Rev. 2003, 103, 2019–2034.
then the solution was heated in MW reactor. First, the temperature was
raised to 80 ˚C in 40 sec, and the reaction was performed for 1 min at this
temperature. Then, the temperature was raised to 200 ˚C in 90 sec, and
the reaction was performed for 3 min at the temperature. After the
completion of the reaction, the solution was concentrated in vacuo to
remove anisole and then the crude material was purified by column
chromatography (hexane-EtOAc = 3:1) to give the 12 (101 mg, 0.35 mmol)
in 59% yield as yellow oil.
2] a) T. Kametani, H. Nemoto, Tetrahedron 1981, 37, 3–16; b) A. S. Chapelon,
D. Moraleda, R. Rodriguez, C. Ollivier, M. Santelli, Tetrahedron 2007, 63,
1
1511–11616; c) P. Gupta, G. Panda, Eur. J. Org. Chem. 2014, 8004–
019; d) R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105, 4730–4756;
8
e) E. G. Mackay, M. S. Sherburn, Synthesis 2015, 1–21; f) M. Kotora, F.
Hessler, B. Eignerova, Eur. J. Org. Chem. 2012, 29–42.
[
3] a) G. Anner, K. Miescher, Helv. Chim. Acta 1948, 31, 2173–2183; b) W. S.
Johnson, R. G. Christensen, J. Am. Chem. Soc. 1951, 73, 5511–5512;
c) W. S. Johnson, D. K. Banerjee, W. P. Schneider, C. D. Gutsche, W.
E. Shelberg, L. J. Chinn, J. Am. Chem. Soc. 1952, 74, 2832–2849; d) W.
S. Johnson, R. G. Christiansen, R. E. Ireland, J. Am. Chem. Soc. 1957,
3rd and 4th pot: To the solution of compound 12 (177.2 mg, 0.60 mmol)
in CH Cl (2.0 ml) was added LiBHEt (1.0 M hexane solution, 600 l, 0.60
2
2
3
mmol) at -78 ˚C. The reaction mixture was stirred for 2 h, then DIBAL (1.0
M, 1.2 ml, 1.2 mmol) was added to the reaction mixture and the reaction
mixture was warmed to 0 ˚C. After stirring it for 12 h, 1 N aq. HCl (4.0 ml)
was added to the reaction mixture at -30˚C and the reaction mixture was
stirred for additional 12 h at room temperature. The reaction mixture was
extracted with EtOAc (5.0 ml) three times. The organic layer was washed
by brine (5.0 ml) twice. The organic layer was dried over Na SO , and
2 4
concentrated in vacuo after filtration. To the solution of crude materials in
DMF (4.0 ml) were added imidazole (245 mg, 3.6 mmol) and TIPSOTf (484
7
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l, 1.8 mmol). The reaction mixture was stirred for 4 h at 60 ˚C, and
quenched by phosphate buffer (4.0 ml, pH 7). The organic material was
extracted with EtOAc (5.0 ml) three times, then the organic layer was
washed by brine (10 ml), dried over Na
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hexane-EtOAc = 10:1) to give compound 17 (160 mg, 0.35 mmol) in 59%
yield as colorless oil.
2 4
SO , and concentrated in vacuo
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2 4 2
5th pot: The compound 17 (84.0 mg, 0.184 mmol), NaH PO •2H O (124.0
mg, 0.796 mmol) and 2-methyl-2-butene (421 l, 3.68 mmol) were
dissolved in tBuOH (2.1 ml) and water (0.53 ml). The solution was cooled
to 0 ˚C, and aq. NaClO
2
(45.6 ml, 43.0 g/L, 0.398 mmol) was added to the
solution. After stirring it for 1 h, acetaldehyde (10 l, 0.184 mmol) was
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Entry for the Table of Contents
FULL PAPER
Pot-Economical Synthesis: A new
efficient synthetic pathway of
Key Topic*
estradiol methyl ether was developed
based on the concept of "Pot-
economy". The key reaction, which is
the organocatalyst mediated
Pot-Economical Synthesis
Author
asymmetric domino Michael/aldol
reaction, was applied to the 5-pot
synthesis of estrogen. The reduction
of the number of pots was found to
be effective in increasing the total
yield of the synthesis.
Seitaro Koshino, Eunsang Kwon, Yujiro
Hayashi*
Page No. – Page No.
Title
Total synthesis of estradiol methyl
ether and its five-pot synthesis
through the use of an organocatalyst
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