Pot Economy in the Total Synthesis of Estradiol Methyl Ether by Using an Organocatalyst

Article abstract of DOI:10.1002/anie.201706046

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a pot-economical manner using five reaction vessels and four purifications. The key reaction is a diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives, containing the A, C, and D rings of steroids, as a single isomer with excellent enantioselectivity. Six reactions such as oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction can be carried out in the last one-pot sequence.

Full text of DOI:10.1002/anie.201706046

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Pot-economical total synthesis of estradiol methyl ether through
the use of an organocatalyst
Authors: Yujiro Hayashi, Seitaro Koshino, Kanna Ojima, and Eunsang
Kwon
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706046
Angew. Chem. 10.1002/ange.201706046
Link to VoR: http://dx.doi.org/10.1002/anie.201706046
http://dx.doi.org/10.1002/ange.201706046

10.1002/anie.201706046
Angewandte Chemie International Edition
COMMUNICATION
Pot-economical total synthesis of estradiol methyl ether through
the use of an organocatalyst
Yujiro Hayashi,*[a] Seitaro Koshino,[a] Kanna Ojima,[a] Eunsang Kwon[b]
Dedicated to Professor Teruaki Mukaiyama in celebration of his 90th birthday (Sotsuju)
Abstract: Enantioselective total synthesis of estradiol methyl ether
structure by using Torgov’s diene via
a
dienamine
has been accomplished in a pot economical manner using five
intermediate.[22] List reported a short synthesis of estrone
through chiral disulfonimide-mediated Torgov cyclization as a
key step.[23] Herein, we describe a pot-economical synthesis of
estradiol methyl ether (1)[24] by using an organocatalyst in a key
transformation.
reaction vessels with four purifications.
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
steroids as a single isomer with excellent enantioselectivity. Six
reactions such as oxidation, hydrogenation, formation of acid
chloride, Friedel-Crafts reaction, deprotection and reduction can be
carried out in the last one-pot sequence.
Our strategy (Scheme 1) is different from the previous
syntheses; installation of all the carbon units necessary for the
steroid was achieved in the first pot with the construction of the
A, C, and D rings of the steroid with complete diastereo- and
enantiocontrol.
We designed the domino reaction[25] of
Efficient and sustainable synthesis has always been a critical
issue for organic chemistry, and basic concepts for the ideal
syntheses[1] involve atom economy,[2] step economy,[3] and
diphenylprolinol silyl ether 4[26] -mediated asymmetric Michael
reaction[27] of nitroalkane 2 and 3-(p-methoxyphenyl)propenal (3),
both of which are commercially available,[28] followed by the
intramolecular aldol reaction, expecting to provide the
bicyclo[4.3.0]nonane structure 9 (Figure 1). After intensive
optimization of this key reaction, it was found that i-PrOH, water
and PhCO2H were suitable solvent and additives, respectively.
Moreover, slow addition of α,β-enal 3 increased the yield. When
the reaction was quenched at this stage, 9 could be isolated in
89% yield. We were delighted to find that 9 was obtained as a
single isomer in nearly optically pure form (>99% ee) with the
correct stereochemistry of the steroids. It should be noted that
five contiguous chiral centers are completely controlled with the
desired configuration.
redox economy.[4]
Recently, we proposed the term “pot
economy”,[5] 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 (–)-oseltamivir,[6] one-pot
syntheses of ABT-341[7] and Baclofen,[8] and three-pot synthesis
of PGE1 methyl ester.[9] Cermizine B,[10] epoxyisoprostanes,[11]
and arborescidine C[12] have also been synthesized efficiently in
a pot-economical approach by other groups.
Steroids, with
a tetracyclic molecular framework, have
In the synthesis of estradiol methyl ether (1), without isolation
of 9, KCN, CS2 and MeI were added in the same reaction vessel
for the stereoselective addition of the cyanide anion to the
aldehyde moiety, followed by the formation of xanthate ester 10.
Dehydration proceeded upon the further addition of SOCl2 and
pyridine in the same pot to afford 5 in 78% yield from 2 and 3 in
the first pot. The relative and absolute configurations of 5 were
determined by the X-ray crystallographic analysis (Figure 2).[29]
In this first single-pot set of reactions, all the carbon units
necessary for the synthesis of estradiol methyl ether (1) were
installed successfully.
Reductive removal of both the nitro group and the xanthate
ester moiety of 5 was accomplished at the same time by
reaction with Bu3SnH in the presence of AIBN[30] at 200 °C under
microwave (MW) irradiation for 3 min to afford 6 in 59% yield. It
should be noted that microwave irradiation was essential to
achieve good yield; standard heating using an oil bath afforded
versatile, strong, and important biological activities.[13] Given
their importance in medicine and biology, many synthetic
methods have been developed for the efficient synthesis of
steroids[14] including polyene cyclization,[15] Diels–Alder
reaction,[16] and transition-metal-mediated reactions.[17]
Organocatalysts[18] have been successfully employed in the
synthesis of steroids. The proline-mediated intramolecular aldol
reaction, reported in 1971,[19] is
a landmark discovery in
organocatalysis. This approach is effective for the synthesis of
the Wieland–Miescher ketone, a key intermediate of the steroid
synthesis.[20] Recently, Hong reported the one-pot synthesis of a
steroid system through organocatalyst-mediated Michael–
Michael–aldol–Henry and Michael–Michael–Henry reactions,[21]
whereas Jørgensen reported the construction of the steroid
[a]
Prof. Dr. Y. Hayashi, S. Koshino, K. Ojima
Department of Chemistry, Graduate School of Science
Tohoku University
the product in moderate yield (34%).
Diastereoselective
reduction of the ketone and conversion of the nitrile group into a
formyl moiety were conducted in a single pot by the successive
addition of LiBHEt3 at –78 °C and DIBAL at 0 °C to provide
hydroxyl aldehyde 7. The next pot involves protection of crude
alcohol 7 with TIPSOTf and imidazole to afford silyl ether 8 in
59% yield from 6. Then, six reactions can be conducted in a
single vessel: Kraus–Pinnick oxidation,[31] hydrogenation, acyl
chloride formation, Friedel–Crafts acylation, deprotection of the
6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
E-mail: yhayashi@m.tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
Prof. Dr. E. Kwon
[b]
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Sendai 980-8578, Japan
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706046
Angewandte Chemie International Edition
COMMUNICATION
10 mol%
O
Ph
O2N
O
Ph
N
O2N
OTMS
H
aq. KCN
CS2, MeI
4
n-Bu3SnH
AIBN
H
O
2
SOCl2
PhCO2H, H2O
+
H
O
i-PrOH, rt
MeCN, -20 ˚C
py, 0 ˚C
MW
anisole, 200 ˚C
MeO
CN
O
S
H
5
S
3
MeO
five reactions in one-pot sequence, 78%
59%
O
OH
OTIPS
TIPSOTf
Imidazole
H
H
DIBAL
LiBHEt3
H
H
H
CH2Cl2, 0 ˚C;
aq. HCl
H
H
CH2Cl2, -78 ˚C
DMF, 60 ˚C
H
MeO
CN
MeO
MeO
O
O
6
7
8
two reactions in one-pot sequence
59%
(3 steps from 6)
OH
NaClO2
NaH2PO4
2-methyl-2-butene
Pd(OH)2
Pd(OH)2
H2
H
(COCl)2
H2
AlCl3
MeOH
H
H
t-BuOH/H2O, 0 ˚C
CH2Cl2, rt
t-BuOH/H2O/AcOH
CH2Cl2, rt
AcOH, rt
MeO
rt
six reactions in one-pot sequence, 55%
estradiol methyl ether (1)
Total 5 pots, Total yield 15%
Scheme 1. Synthesis of estradiol methyl ether (1)
O
OTIPS
O
O2N
O2N
H
H
H
H
OH
CN
H
OH
OH
O
MeO
MeO
O
S
MeO
H
O
S
9
10
11
>99% ee
OTIPS
OH
OTIPS
H
H
H
H
H
O
H
H
H
H
O
OH
Cl
MeO
MeO
MeO
O
12
13
14
Figure 2. The ORTEP diagram of key intermediate 5
Figure 1. Intermediates in the synthesis of estradiol methyl ether (1)
Although the B-ring in 14 was constructed by the
intramolecular Friedel–Crafts acylation from acylchloride 13, it
should be noted that the other regioisomer, 16, was selectively
formed by the intramolecular Houben–Hoesch reaction[35] from
the cyanide derivative 15 in 51% yield (Scheme 2), which would
be generated by the ipso-addition of the p-methoxybenzene
moiety on the activated cyanide, followed by dienone–phenol
rearrangement.
silyl group by the addition of MeOH,[32] and reduction of benzyl
ketone were accomplished sequentially to afford estradiol
methyl ether (1) in 55% yield in a single pot.
In the
transformation from 11 into 12, the stereoselective
hydrogenation proceeds from the α-face because the β-face
was covered by the bulky silyl substituent.[33] The physical
properties of synthetic estradiol methyl ether (1) are identical in
all respects to the reported data.[34] Thus, estradiol methyl
ether (1) was synthesized in five pots with four purification
steps.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706046
Angewandte Chemie International Edition
COMMUNICATION
groups such as nitro and hydroxyl groups at suitable
positions,[36] it constitutes a useful synthetic intermediate for the
synthesis of steroid derivatives. Two reductions (LiBHEt3 and
DIBAL) can be conducted in the same pot. Six reactions,
namely oxidation, hydrogenation, formation of acid chloride,
Friedel–Crafts reaction, deprotection, and reduction, can be
carried out in the last one-pot sequence.
OH
OTBS
Sc(OTf)3
H
H
MeO
H
H
MsOH/CH2Cl2 (1:1), rt, 2.5 h;
H
H
H2O, 60 °C, 3h
MeO
CN
51%
O
15
16
Scheme 2. Rearrengement of methoxy group in Houben-Hoesch reaction
Acknowledgements
We then investigated the generality of the first domino
reaction of Michael and aldol reactions. As summarized in
Table 1, the reaction has wide generality; for the substituents at
the 3-position of propenal, not only electron-rich p-
methoxyphenyl and 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 are solid, and they precipitated
out as the reaction proceeded.
This work was supported by JSPS KAKENHI Grant Number
JP16H01128 in Middle Molecular Strategy.
Keywords: organocatalyst • steroid • domino reaction • total
synthesis• asymmetric synthesis
References
[1] T. Gaich, P. S. Baran, J. Org. Chem. 2010, 75, 4657.
[2] B. M. Trost, Science 1991, 254, 1471.
[3] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.
2008, 41, 40.
Table 1. The generality of the domino Michael-aldol reaction[a]
[4] N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. 2009, 121,
2896; Angew. Chem. Int. Ed. 2009, 48, 2854.
10 mol%
Ph
[5] a) P. A. Clarke, S. Santos, W. H. C. Martin, Green Chem. 2007, 9, 438; b)
C. Vaxelaire, P. Winter, M. Christmann, Angew. Chem. 2011, 123,
3685; Angew. Chem. Int. Ed. 2011, 50, 3605; c) Y. Hayashi, Chem.
Sci. 2016, 7, 866.
Ph
N
4
O
OTMS
H
O
O2N
Ar
PhCO2H, H2O
O
O2N
H
+
[6] a) H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. 2009, 121, 1330;
Angew. Chem. Int. Ed. 2009, 48, 1304; b) H. Ishikawa, T. Suzuki, H.
Orita, T. Uchimaru, Y. Hayashi, Chem. Eur. J. 2010, 16, 12616; c) T.
Mukaiyama, H. Ishikawa, H. Koshino, Y. Hayashi, Chem. Eur. J. 2013,
19, 17789; d) Y. Hayashi, S. Ogasawara, Org. Lett. 2016, 18, 3426; e)
S. Ogasawara, Y. Hayashi, Synthesis 2017, 49, 424.
i-PrOH, rt
Ar
H
OH
O
O
H
2
Entry
Ar
dr
Yield [%][b]
ee [%][c]
>99
98
1
2
3
4
5
6
7
p-MeOC6H4-
tolyl
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
89
86
91
78
94
85
81
[7] H. Ishikawa, M. Honma, Y. Hayashi, Angew. Chem. 2011, 123, 2876;
Angew. Chem. Int. Ed. 2011, 50, 2824.
[8] Y. Hayashi, D. Sakamoto, D. Okamura, Org. Lett. 2016, 18, 4.
[9] Y. Hayashi, S. Umemiya, Angew. Chem. 2013, 125, 3534; Angew. Chem.
Int. Ed. 2013, 52, 3450.
Ph
97
[10] B. Bradshaw, C. Luque-Corredera, J. Bonjoch, Chem. Commun. 2014,
50, 7099.
p-FC6H4-
p-ClC6H4-
p-BrC6H4-
o-FC6H4-
97
98
[11] J. Weng, S. Wang, L.-J. Huang, Z.-Y. Luo, G. Lu, Chem. Commun. 2015,
51, 10170.
98
[12] V. M. Sheth, B.-C. Hong, G.-H. Lee, Org. Biomol. Chem. 2017, 15, 3408.
[13] J.-F. Biellmann, Chem. Rev. 2003, 103, 2019.
98
[14] a) T. Kametani, H. Nemoto, Tetrahedron 1981, 37, 3; b) A. S. Chapelon,
D. Moralëda, R. Rodriguez, C. Ollivier, M. Santelli, Tetrahedron 2007,
63, 11511; c) P. Gupta, G. Panda, Eur. J. Org. Chem. 2014, 79, 8004.
[15] R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105, 4730.
[16] E. G. Mackay, M. S. Sherburn, Synthesis 2015, 47, 1.
[17] M. Kotora, F. Hessler, B. Eignerova, Eur. J. Org. Chem. 2012, 29.
[18] Selected reviews on organocatalysis: a) Asymmetric Organocatalysis 1;
Lewis Base and Acid Catalysts (Ed.: B. List), Thieme, Stuttgart, 2012;
b) Comprehensive Enantioselective Organocatalysis: Catalysts,
Reactions, and Applications (Ed.: P. I. Dalko), Wiley-VCH, Weinheim,
2013.
[a] Unless otherwise shown, the reaction was performed by employing
nitroalkane (1.0 mmol), α,β-enal (1.2 mmol), organocatalyst 4 (0.1 mmol, 10
mol%), PhCO2H (0.2 mmol), water (3.0 mmol) and i-PrOH (6.5 mL) at 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)3 and TsOH. See supporting
information for details.
In summary, the enantioselective total synthesis of estradiol
methyl ether (1) has been accomplished in five reaction vessels
with four purification steps. The key reaction is a domino
reaction of diphenylprolinol silyl ether-mediated Michael
reaction of nitroalkane 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 continuous chiral centers are completely controlled with the
desired configuration. This key reaction has a wide generality.
Given that the domino product possesses several functional
[19] a) Z. G. Hajos, D. R. Parrish, German Patent DE 2102623, July 29,
1971; b) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; c)
U. Eder, G. Sauer, R. Wiechert, German Patent DE 2014757, Oct 7,
1971; d) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83,
492; Angew. Chem. Int. Ed. 1971, 10, 496.
[20] B. Bradshaw, J. Bonjoch, Synlett 2012, 337.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706046
Angewandte Chemie International Edition
COMMUNICATION
[21] a) D.-H. Jhuo, B.-C. Hong, C.-W. Chang, G.-H. Lee, Org. Lett. 2014, 16,
2724. b) C.-H. Peng, B.-C. Hong, A. Raja, C.-W. Chang, G.-H. Lee,
RSC Adv. 2016, 6, 95314.
[26] a) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005, 117,
4284; Angew. Chem. Int. Ed. 2005, 44, 4212; b) M. Marigo, T. C.
Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117,
804; Angew. Chem. Int. Ed. 2005, 44, 794.
[22] K. S. Halskov, B. S. Donslund, S. Barfüsser, K. A, Jørgensen, Angew.
Chem. 2014, 126, 4221; Angew. Chem. Int. Ed. 2014, 53, 4137.
[23] S. Prëvost, N. Duprë, M. Leutzsch, Q. Wang, V. Wakchaure, B. List,
Angew. Chem. 2014, 126, 8915; Angew. Chem. Int. Ed. 2014, 53,
8770.
[27] H. Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2007, 9, 5307.
[28] CAS number: 2: 1020110-71-7, 3: 1963-36-6. Commercial source, see
Supporting Information for details.
[29] A CIF file for 5 was deposited with the Cambridge Crystallographic Data
Centre. CCDC 1546171 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
[24] For reviews on total syntheses of estrogens, see: a) F. J. Zeelen, Nat.
Prod. Rep. 1994, 11, 607. b) M. B. Groen, F. J. Zeelen, Recl. TraV.
Chim. Pays-Bas 1986, 105, 465. For recent selected examples, see:
c) K. Tanaka, H. Nakashima, T. Taniguchi, K. Ogasawara, Org. Lett.
2000, 2, 1915. d) K. Hanada, N. Miyazawa, K. Ogasawara, Chem.
Pharm. Bull. 2003, 51, 104. e) S. B. Tsogoeva, G. Durner, M. Bolte, M.
Gobel, Eur. J. Org. Chem. 2003, 1661. f) Q. Y. Hu, P. D. Rege, E. J.
Corey, J. Am. Chem. Soc. 2004, 126, 5984. g) D. Soorukram, P.
Knochel, Org. Lett. 2007, 9, 1021. h) Y. -Y. Yeung, R. -J. Chein, E. J.
Corey, J. Am. Chem. Soc. 2007, 129, 10346. i) P. Herrmann, M.
Buděšínský, M. Kotora, J. Org. Chem 2008, 73, 6202. j) M. Weimar, G.
Dürner, J. W. Bats, M. W. Göbel, J. Org. Chem. 2010, 75, 2718. k) V.
Foucher, B. Guizzardi, M. B. Groen, M. Light, B. Linclau, Org. Lett.
2010, 12, 680. l) Y. -P. Xue, W. -D. Z. Li, J. Org. Chem. 2011, 76, 57.
[25] Review, see; a) C. Grondal, M. Jeanty, D. Enders, Nature Chem. 2010, 2,
167; b) L. Albrecht, H. Jiang, K. A. Jørgensen, Angew. Chem. 2011,
123, 8642; Angew. Chem. Int. Ed. 2011, 50, 8492; c) H. Pellissier, Adv.
Synth. Catal. 2012, 354, 237; d) C. M. R. Volla, I. Atodiresei, M.
Rueping, Chem. Rev. 2014, 114, 2390; d) B.-C. Hong, A. Raja, V. M.
Sheth, Synthesis 2015, 47, 3257.
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[30] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. I 1975,
1574. b) N. Ono, H. Miyake, R. Tamura, A. Kaji, Tetrahedron Lett.
1981, 22, 1705. c) D. D. Tanner, E. V. Blackburn, G. E. Diaz, J. Am.
Chem. Soc. 1981, 103, 1557.
[31] a) G. A. Kraus, M. J. Taschner, J. Org. Chem. 1980, 45,1175. b) B. S.
Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981, 37, 2091.
[32] MeOH reacts with AlCl3 to generate HCl, which deprotects of the silyl
group.
[33] A. Abad, C. Agullo, M. Arno, L. R. Domingo, R. J. Zaragoza, J. Org.
Chem. 1990, 55, 2369.
[34] R. C. Cambie, T. D. R. Manning, J. Chem. Soc. C, 1968, 2603.
[35] G. A. Olah, Friedel-Crafts and related Reactions, Interscience Publishers,
New York, 1964.
[36] As for the 14β-hydroxysteroids, see; C. Peter, B. Ressault, P. Geoffroy,
M. Miesch, Chem. Eur. J. 2016, 22, 10808, and the references cited
therein.
COMMUNICATION
Y. Hayashi*, S. Koshino, K. Ojima, E.
Kwon
O
10 mol%
O
O2N
Ar
Ph
OH
H
Ph
OTMS
O2N
N
H
H
OH
O
O
Page No. – Page No.
H
+
H
H
up to 91% yield
single diastereomer
up to >99% ee
7 examples
Domino
Michael/Aldol
Total 5 pots
Total yield 15%
O
MeO
Title
estradiol methyl ether
Ar
H
Estradiol methyl ether was synthesized via five pots with four purifications using
diphenylprolinol silyl ether mediated Michael reaction as a key step. The last one-
pot sequence of the reaction involves six reactions.
This article is protected by copyright. All rights reserved.