A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters by tandem acetylation-E1CB reaction

Article abstract of DOI:10.1248/cpb.c18-00666

A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in β-hydroxy esters, furnishing α,β-unsaturated esters in shorter steps than the previous method: an acetylation of β-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,β-unsaturated esters.

Full text of DOI:10.1248/cpb.c18-00666

Vol. 67, No. 1
Chem. Pharm. Bull. 67, 71–74 (2019)
71
Note
A Facile and Convenient Synthesis of Trisubstituted (E)-α,β-Unsaturated
Esters by Tandem Acetylation-E1cB Reaction
,a
Minoru Ozeki,* Ayumi Hachino,a Takashi Shigeta,a Aya Niki,a Natsuko Kobayashi,a
Hideki Mizutani,b Akihiro Nakamura,b Ayano Horie,b Kenji Arimitsu,b Tetsuya Kajimoto,c
,a
Shinzo Hosoi,b Hiroki Iwasaki,b Naoto Kojima,b Masayuki Yamashita,b and Ikuo Kawasaki*
a Department of Medicinal and Synthetic Chemistry, Faculty of Pharmaceutical Sciences, Mukogawa Women’s
b
University; 11–68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663–8179, Japan: Department of Pharmaceutical
Manufacturing Chemistry, Kyoto Pharmaceutical University; 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto
c
607–8414, Japan: and Medicinal Organic Chemistry Laboratory, College of Pharmaceutical Sciences, Ritsumeikan
University; 1–1–1 Noji-higashi, Kusatsu, Shiga 525–8577, Japan.
Received August 29, 2018; accepted October 22, 2018
A facile and convenient synthesis of trisubstituted (E)-α,β-unsaturated esters was developed by improv-
ing our previously established method. The new method circumvented the separation of the intermediates,
which have an activating group of the hydroxyl group in β-hydroxy esters, furnishing α,β-unsaturated esters
in shorter steps than the previous method: an acetylation of β-hydroxy group and subsequent E1cB reaction
proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the sub-
strate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of vari-
ous trisubstituted (E)-α,β-unsaturated esters.
Key words stereoselective synthesis; E1cB reaction; tandem acetylation-E1cB reaction; trisubstituted (E)-
α,β-unsaturated ester
for the synthesis of trisubstituted (E)-α,β-unsaturated esters
Introduction
Trisubstituted (E)-α,β-unsaturated esters are one of the most to date.21–26) However, the Baylis–Hillman reaction commonly
important substrates in organic reactions, such as the Michael requires a long reaction time, which is a disadvantage for easy
addition or the Diels–Alder reaction.1–5) Natural products hav- access to the desired compound. Synthesis involving the ste-
ing such structures as partial units have attracted organic reoselective elimination of α-substituted β-hydroxy carbonyl
chemists as well as biologists because of their potent biological derivatives has also been reported by several groups.5,27–31)
and pharmacological activities.6–11) It is well known that the Among them, the direct conversion of β-hydroxy carbonyl
geometry of α,β-unsaturated esters is reflected in the stereo- compounds into α,β-unsaturated carbonyl compounds is
chemistry of the product in various stereoselective reactions. a promising method for the practical synthesis: Concellón
In addition, the biological activities of bioactive compounds et al. reported the elimination reaction of SmI2 and α-halo-β-
including a natural product could be dramatically affected hydroxy esters,27) in which the preliminary preparation of
by the geometry of the carbon–carbon double bond.6,9,12) The α-halo-β-hydroxy esters as the substrate of the elimination re-
Wittig reaction and the Horner–Wadsworth–Emmons reaction action was required. The synthesis involving the stereospecific
have been classically employed as reliable methods for the dehydration of simple β-hydroxy ester derivatives by ethyldi-
synthesis of α,β-unsaturated carbonyl compounds; however, methylaminopropylcarbodiimide (EDC)/CuCl2 was reported
these reactions include tedious procedure such as the prelimi- by Ohmizu and colleagues.28,29) In that reaction, the use of
nary preparation of humidity-sensitive ylide derivatives and a single diastereomer of β-hydroxy esters was essential to
removal of large amounts of byproducts, e.g., phosphonates or achieve high E/Z stereoselectivity. Marcantoni and colleagues
phosphine oxides.13–16) Thus, many studies on the stereoselec- reported the stereoselective elimination reaction of β-hydroxy
tive synthesis of trisubstituted (E)-α,β-unsaturated carbonyl carbonyl compounds that used CeCl3-7H2O/NaI30); however,
compounds have been carried out. For example, E-selective that reaction had a limitation that a tert-butyl ester derivative
synthesis of trisubstituted (E)-α,β-unsaturated esters based could not be used as the substrate.
on chemistry of ynolate intermediates were reported by Kow-
Meanwhile, we have reported a practical and highly E
alski and Shindo, independently.17,18) Verkade and colleagues stereoselective synthesis of trisubstituted (E)-α,β-unsaturated
reported the synthesis of trisubstituted (E)-α,β-unsaturated es- esters32) (Chart 1a). Our method consists of three well-
ters by utilizing expensive pro-azaphosphatrane as the strong known reactions, i.e., the aldol reaction, the acetyla-
base; however the method was not applicable to the synthesis tion of the β-hydroxy group, and the E1cB reaction using
of α,β-unsaturated esters bearing an aliphatic chain at the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Herein, we em-
β-position.19) Ma and colleagues reported synthesis by an Ni phasize that the method does not require separation of the
complex-catalyzed carbonylation of alkyne, in which a de- diastereomeric mixture of β-hydroxy esters prior to the E1cB
crease in regioselectivity was observed in several cases.20) The reaction. Thus, we endeavored to develop a more facile syn-
Baylis–Hillman reaction has been utilized as the key reaction thesis of trisubstituted (E)-α,β-unsaturated esters by improv-
*To whom correspondence should be addressed. e-mail: ozekim@mukogawa-u.ac.jp; ikuo_k@mukogawa-u.ac.jp
© 2019 The Pharmaceutical Society of Japan

72
Chem. Pharm. Bull.
Vol. 67, No. 1 (2019)
Chart 1. Synthesis of Trisubstituted (E)-α,β-Unsaturated Esters by Our Previous Work and This Work
Table 1. Optimization Study of Direct E1cB Reaction
3a
Entry
Ac2O (eq) DMAP (eq)
Base (eq)
Solvent
Temp./time
2a yield (%)
Yield (%)
E/Za)
1
2
3
5.0
2.5
1.1
0.1
0.1
0.1
1
—
Pyridine
Toluene
Toluene
r.t./1h→120°C/2h
r.t./0.5h→130°C/2h
130°C/4h
—
95
—
86
—
—
DBU (5.0)
DBU (5.0)
98/2
99/1
98
a) Selectivities were determined by H-NMR measurement.
ing our previous method (Chart 1b): the new method furnished ined the synthesis of trisubstituted (E)-α,β-unsaturated esters
trisubstituted α,β-unsaturated esters in shorter steps than the 3 having an aromatic ring at the β-position. Excellent yields
previous method by conducting an activation of the β-hydroxy and high stereoselectivities were observed regardless of the
group in β-hydroxy ester derivatives by acetylation and the electrophilic property of the substituent on the aromatic ring
successive E1cB reaction in tandem.
in all cases (entries 1–5). The reactions using 1g–i possessing
a heteroaromatic ring at the β-position also provided 3g–i in
good to excellent yields with high stereoselectivities (entries
Results and Discussion
First, to optimize the reaction conditions, we examined the 6–8). Next, to examine the influence of an α-substituent,
synthesis of trisubstituted (E)-α,β-unsaturated ester 3a by reactions using a substrate having a bulkier substituent than
the stereoselective E1cB reaction of α-substituted-β-hydroxy a methyl group were conducted (entries 9–12). β-Hydroxy
ester 1a (Table 1), which was conventionally prepared from esters 1j–l having ethyl, benzyl, and isopropyl groups as the
the aldol reaction of tert-butyl propionate with benzaldehyde α-substituent afforded desired compounds 3j–l in good to
in 83% yield with dr 1.5:1 diastereomeric mixture. When excellent yields with relatively high stereoselectivities (entries
diastereomeric mixture 1a was subjected to the reaction using 9–11). On the other hand, the reaction of substrate 1m having
acetic anhydride (Ac2O) and a catalytic amount of 4-dimeth- a phenyl group as the α-substituent resulted in an unsatisfacto-
ylaminopyridine (DMAP) in pyridine under reflux conditions, ry yield because of the decomposition of 1m by the retro-aldol
acetylated compound 2a was obtained in 86% yield without reaction. Thus, we examined a one-pot reaction that consisted
any other products (entry 1). This result indicated that the ba- of the acetylation of the β-hydroxy group under mild reaction
sicity of pyridine was insufficient for the E1cB reaction. Next, conditions followed by the E1cB reaction of the acetylated in-
we conducted the reaction in the presence of DBU as the base, termediate in a vessel: After 1m was acetylated by Ac2O and
i.e., 1a was subjected to the reaction using 5eq of DBU in the DMAP without DBU in toluene at room temperature, the sub-
presence of Ac2O (2.5eq) and DMAP (0.1eq) in toluene reflux sequent E1cB reaction was carried out by the addition of DBU
(130°C), and desired compound 3a was obtained in 95% yield under reflux conditions. As a result, the desired compound 3m
with E/Z=98/2 (entry 2). Moreover, we succeeded in reduc- was provided in excellent yield with good geoselectivity in
ing the amount of Ac2O to 1.1eq from 2.5eq under similar one-pot (entry 12). Finally, we explored the applicability of the
reaction conditions to entry 2 (entry 3). It should be noted synthesis to compounds bearing an aliphatic substituent, the
that the present method was capable of the one-step conver- reports of which have been few to date24) (entries 13–15). In
sion of 1 into 2 without the separation of a compound having the cases of substrates 1n and 1o bearing n-hexyl or c-hexyl
an activated leaving group prior to the E1cB reaction: tandem groups, both reactions afforded desired compounds 3n and
acetylation-E1cB reaction.
3o in good yields with high stereoselectivities (entries 13 and
Having established the optimized reaction conditions, we set 14). Unfortunately, the reaction using 1p possessing a t-butyl
out to explore the substrate scope (Table 2). First, we exam- group resulted in an unsatisfactory yield because the acetyla-

Vol. 67, No. 1 (2019)
Chem. Pharm. Bull.
73
Table 2. Scope and Limitations
aSelectivities were determined by 1H-NMR measurement. bAfter the acetylation at room temperature was
c
completed, the reaction was refluxed in the presence of DBU. Yield and E/Z ratio of 3 by “previous method”
meant two-step yield and E/Z ratio from 2 to 3 in our previous report.32)
tion of the β-hydroxy group did not procced successfully due esters more easily than the previous method by tandem acet-
to the bulkiness of tert-butyl group at β-position. Moreover, ylation-E1cB reaction: The activation of the β-hydroxyl group
the partial decomposition of 1p was observed under the reflux in 1 by the acetylation followed by E1cB reaction proceeded in
condition used excess reagents (Ac2O, DBU) to improve the tandem, enabling to circumvent the separation of intermedi-
reactivity. Thus, we examined the synthesis by a similar one- ates having an activated leaving group before the E1cB. Also,
pot reaction to the case of compound 3m: 1p was subjected to the new method can employ diastereomeric mixture 1 as the
the acetylation using Ac2O and DMAP without DBU in tolu- substrate for the E1cB reaction as well as our previous method
ene at room temperature followed by the E1cB reaction in the and has a wide substrate scope for the synthesis of various
presence of DBU under reflux conditions, affording desired trisubstituted (E)-α,β-unsaturated esters. Further studies of the
3p in higher yield than that of the previous method (entry 15). application to the synthesis of multisubstituted alkenes and the
Regarding the stereoselectivity on the elimination reaction asymmetric synthesis using these α,β-unsaturated esters are in
of diastereomeric mixture 1, we consider that the stereoselec- progress.
tivity of the product would be determined on the elimination
step not isomerization of the product under thermal reaction
Acknowledgments This research was financially support-
condition.33) As we reported previosly,32) the E1cB reaction ed in part by the Ministry of Education, Culture, Sports, Sci-
predominantly proceed over an E2 reaction in the present ence, and Technology of Japan (MEXT)-Supported Program
elimination reaction; actually, there are reports that use ei- for the Strategic Research Foundation at Private Universities,
ther a p-toluenesulfonyl group or a methanesulfonyl group as JSPS KAKENHI Grant Number JP22590024, and a Strategic
stronger leaving group than the acetyl leaving group, which Research Foundation Grant-Aided Project for Private Univer-
used in our reaction, decreased the selectivity.5,31) Thus, high sities from MEXT, Grant Number S1511024L.
stereoselectivity could be achieved in spite of the fact that
the substrate of diastereomeric mixture was employed in the
elimination reaction.
Conflict of Interest The authors declare no conflict of
interest.
In conclusion, we succeeded in the development of a facile
and convenient synthesis of trisubstituted (E)-α,β-unsaturated
Supplementary Materials The online version of this ar-
esters based on our previous method. The new method is ticle contains supplementary materials.
capable of the synthesis of trisubstituted (E)-α,β-unsaturated

74
Chem. Pharm. Bull.
Vol. 67, No. 1 (2019)
17) Kowalski C. J., Sakdarat S., J. Org. Chem., 55, 1977–1979 (1990).
18) Shindo M., Sato Y., Shishido K., Tetrahedron Lett., 39, 4857–4860
(1998).
References and Notes
1) Davies S. G., Ichihara O., Walters A. S., J. Chem. Soc., Perkin
Trans. 1, 1994, 1141–1147 (1994).
19) Kisanga P., D’Sa B., Verkade J., Tetrahedron, 57, 8047–8052 (2001).
20) Li S., Yuan W., Ma S., Angew. Chem. Int. Ed., 50, 2578–2582
(2011).
21) Basavaiah D., Sarma P. K. S., Bhavani A. K. D., J. Chem. Soc.
Chem. Commun., 1994, 1091–1092 (1994).
22) Basavaiah D., Krishnamacharyulu K., Hyma R. S., Sarma P. K. S.,
Kumaragurubaran N., J. Org. Chem., 64, 1197–1200 (1999).
23) Ravichandran S., Synth. Commun., 31, 2055–2057 (2001).
24) Fernades L., Bortoluzzi A. J., Sá M. M., Tetrahedron, 60, 9983
(2004).
25) Das B., Chowdhury N., Banerjee J., Majhi A., Tetrahedron Lett., 47,
6615–6618 (2006).
26) Das B., Banerjee J., Chowdhury N., Majhi A., Chem. Pharm. Bull.,
54, 1725–1727 (2006).
27) Concellón J. M., Pérez-Andrés J. A., Rodríguez-Solla H., Angew.
Chem. Int. Ed., 39, 2773–2775 (2000).
28) Sai H., Ohmizu H., Tetrahedron Lett., 40, 5019–5022 (1999).
29) Sai H., Ogiku T., Ohmizu H., Tetrahedron, 63, 10345–10353 (2007).
30) Bartoli G., Bellucci M. C., Petrini M., Marcantoni E., Sambri L.,
Torregiani E., Org. Lett., 2, 1791–1793 (2000).
31) Heissler D., Jenn T., Nagano H., Tetrahedron Lett., 32, 7587–7590
(1991).
32) Ozeki M., Egawa H., Kuse A., Takano T., Yasuda N., Mizutani H.,
Izumiya S., Nakashima D., Arimitsu K., Miura T., Kajimoto T.,
Hosoi S., Iwasaki H., Kojima N., Node M., Yamashita M., Synthe-
sis, 47, 3392–3402 (2015).
33) In our previous study, the acetylation, in which DBU was absent,
of 1l spontaneously afforded (E)-α,β-unsaturated ester 3l with
high selectivity. This result indicated that no an isomerization by
a conjugate addition of DBU was included in the stereoselectivity
determination step. (See ref. 32.)
2) Villa M.-J., Warren S., J. Chem. Soc., Perkin Trans. 1, 1994, 1569
(1994).
3) Sturm T., Weissensteiner E., Spindler F., Adv. Synth. Catal., 345,
160–164 (2003).
4) Huang J., Corey E. J., Org. Lett., 5, 3455–3458 (2003).
5) Langenhan J. M., Gellman S. H., J. Org. Chem., 68, 6440–6443
(2003).
6) Watanabe T., Hayashi K., Yoshimatsu S., Sakai K., Takeyama S.,
Takashima K., J. Med. Chem., 23, 50–59 (1980).
7) D’Auria M. A., Minale L., Riccio R., Chem. Rev., 93, 1839–1895
(1993).
8) Senokuchi K., Nakai H., Nakayama Y., Odagaki Y., Sakaki K.,
Kato M., Maruyama T., Miyazaki T., Ito H., Kamiyasu K., Kim S.,
Kawamura M., Hamanaka N., J. Med. Chem., 38, 2521–2523 (1995).
9) Senokuchi K., Nakai H., Nakayama Y., Odagaki Y., Sakaki K.,
Kato M., Maruyama T., Miyazaki T., Ito H., Kamiyasu K., Kim S.,
Kawamura M., Hamanaka N., J. Med. Chem., 38, 4508–4517 (1995).
10) Franklin A. S., J. Chem. Soc., Perkin Trans. 1, 1999, 3537–3554
(1999).
11) Basavaiah D., Krishnamacharyulu M., Hyma R. S., Sarma P. K. S.,
Kumaragurubaran N., J. Org. Chem., 64, 1197–1200 (1999).
12) Marfat A., McGuirk P. R., Helquist P., J. Org. Chem., 44, 3888–
3901 (1979).
13) Mouloungui Z., Elmestour R., Delmas M., Gaset A., Tetrahedron,
48, 1219–1232 (1992).
14) Kojima S., Takagi R., Akiba K., J. Am. Chem. Soc., 119, 5970–5971
(1997).
15) Ando K., J. Org. Chem., 62, 1934–1939 (1997).
16) Sano S., Yokoyama K., Fukushima M., Yagi T., Nagao Y., Chem.
Commun., 1997, 559–560 (1997).