Synthesis of conjugated multiunsaturated thioesters via one-pot TiCl4-promoted aldol condensation

Article abstract of DOI:10.1016/j.tetlet.2020.152280

TiCl₄-promoted aldol condensations of S-4-chlorophenyl thioesters with enals or dienals led to the production of dienyl or trienyl thioesters in good yields. Due to good crystallinity, products with high E/Z ratios were obtained by simple filtr

Full text of DOI:10.1016/j.tetlet.2020.152280

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Synthesis of conjugated multiunsaturated thioesters via one-pot TiCl -promo‐
4
ted aldol condensation
Alex Boateng, Tokifumi Harada, Yasuhiko Ashikari, Makoto Nakajima,
Masaharu Sugiura
PII:
S0040-4039(20)30747-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152280
TETL 152280
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 June 2020
17 July 2020
21 July 2020
Please cite this article as: Boateng, A., Harada, T., Ashikari, Y., Nakajima, M., Sugiura, M., Synthesis of
conjugated multiunsaturated thioesters via one-pot TiCl -promoted aldol condensation, Tetrahedron Letters
4
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152280
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Synthesis of conjugated multiunsaturated
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thioesters via one-pot TiCl
4
-promoted aldol
condensation
a,#
b,#
b
b
a,
Alex Boateng , Tokifumi Harada, Yasuhiko Ashikari, Makoto Nakajima, Masaharu Sugiura 

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of conjugated multiunsaturated thioesters via one-pot TiCl -promoted aldol
4
condensation
a,#
b,#
b
b
a,
Alex Boateng , Tokifumi Harada , Yasuhiko Ashikari , Makoto Nakajima , Masaharu Sugiura 
a
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
4
TiCl -promoted aldol condensations of S-4-chlorophenyl thioesters with enals or dienals led to
the production of dienyl or trienyl thioesters in good yields. Due to good crystallinity, products
with high E/Z ratios were obtained by simple filtration in many cases. Reduction of the thioester
moiety by DIBAL-H afforded the corresponding unsaturated aldehydes while suppressing the
E/Z-isomerization and overreduction. The method was applied to the preparation of simple
synthetic intermediates of natural products such as spectinabilin and aureothin.
Available online
Keywords:
Aldol condensation
Thioester
2
009 Elsevier Ltd. All rights reserved.
Unsaturated carbonyl compound
Polyene
—
——

Corresponding author. E-mail: msugiura@ph.sojo-u.ac.jp
These authors contributed equally to the work.
#

2
Tetrahedron
Introduction
Results and Discussion
Conjugated polyene structures are found in natural products
and are often synthesized from polyenyl carbonyl compounds
1,2]. For example, the total synthesis of spectinablin by Baldwin
A starting material, enal 2a was prepared in high yield by
aldol condensation between propionaldehyde and p-
nitrobenzaldehyde using Bu NOH as the catalyst [7]. However,
4
[
and co-workers was achieved starting from dienal 1a (Fig. 1) [3].
Dienal 1a was prepared from p-nitrobenzaldehyde through an
further aldol condensation between propionaldehyde and 2a
under the same conditions did not afford dienal 1a. The self-
condensation of propionaldehyde was predominant in this case,
indicating that enal 2a is less electrophilic than propionaldehyde.
Therefore, a one-pot TiCl -promoted aldol condensation [5] was
4
applied between enal 2a and S-phenyl propanethioate (4a).
Thioester 4a in dichloromethane was treated successively with
iterative
Horner-Wadsworth-Emmons
reaction/DIBAL-H
reduction/Swern oxidation sequence. The recent synthesis of
aureothin by Paolis and co-workers used -bromodienoate 3
prepared by the Wittig reaction of enal 2a [4].
4 3
TiCl and Bu N at –78 °C. After 30 min at that temperature, solid
enal 2a was added in one portion to the resulting deep purple
solution (the aldol step). After 1 h at –78 °C, pyridine (5 equiv)
was added to promote the elimination step. The cooling bath was
then removed from the experimental set-up and the mixture was
2
stirred at rt. After stirring for more than 1 h, Celite® and Et O
were successively added to promote precipitation of the
ammonium (pyridinium) and titanium residue. After filtration
and concentration, the crude product was treated with
2
MeOH/H O to crystalize the desired product. Pure (2E,4E)-
thioester 5a was obtained by filtration in good yield (Table 1,
entry 1). The residue after crystallization was further purified by
column chromatography to give a mixture of (2E,4E)- and
(2Z,4E)-5a. The yield and 2E/2Z ratio obtained by
chromatography are given in parenthesis in Table 1.
Table 1. TiCl -promoted aldol condensation of various
thioester 4 with enal 2a.
4
Scheme 1. Examples of polyene natural product synthesis
from polyenyl carbonyl compounds.
Recently, we reported the one-pot synthesis of -
disubstituted -unsaturated ketones or thioesters via the TiCl -
4
promoted aldol condensation between simple ketones or between
ketones and S-phenyl thioacetate (Scheme 2a) [5]. Herein, we
report that dienyl and trienyl thioesters 5 and 6 can be prepared
Entr
y
4
Ar’
5
Yield (%)a
2E/2Zb
4
via the TiCl -promoted aldol condensation between S-aryl
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Ph
5a
5b
5c
5d
5e
5f
74 (13)
– (89)
86 (8)
83 (–)
69 (–)
74 (–)
100:0 (63:37)
– (94:6)
100:0 (92:8)
100:0 (–)
100:0 (–)
98:2 (–)
thioester 4 and enal 2 or between dienal 1 and thioester 4’,
respectively (Scheme 2b) [6]. Thioesters 5 and 6 with high E/Z
ratios were obtained by simple filtration in many cases. DIBAL-
H reduction of 5 and 6 gave the corresponding conjugated
aldehydes such as dienal 1 while maintaining the E/Z ratio.
2 6 3
2,5-Me C H
4-ClC
4-BrC
4-NO
4-MeOC
6
H
4
6
H
4
2
C
6
H
H
6 4
4
a
Yields of 5 obtained by crystallization. The data after column
chromatography of the crystallization residue are given in
parenthesis.
b
The 2E/2Z ratio of 5 obtained by crystallization. The data after
column chromatography of the crystallization residue are given in
parenthesis.
According to the above procedure, the effect of the aryl group
(
Ar’) of thioester 4 was examined (Table 1, Entries 2–6). The
reaction tolerated both electron-poor and -rich Ar’ groups
Entries 2–6). Among Ar’ groups tested, 4-chlorophenyl group
gave the best result (Entry 3). The corresponding dienyl thioester
2E,4E)-5c was obtained as yellow crystals in geometrically pure
(
(
form. Bulky S-2,5-dimethylphenyl thioester 4b provided a good
yield, however product 5b was difficult to purify by
crystallization (Entry 2).
4
Scheme 2. TiCl -promoted aldol condensation for the
synthesis of unsaturated carbonyl compounds.
The reduction of thioester 5a–f to dienal 1a was next
investigated
(Table
2).
A
solution
of
5
in
dichloromethane/cyclohexane (1:1) was treated with DIBAL-H at

3
–
78 °C. After 30 min, 6 M NaOH/MeOH solution was added to
(–)
)
quench the reaction. Use of the strong base was important to
suppress the E/Z isomerization. Among 5a–f, S-4-chlorophenyl
thioester 5c gave the best result in terms of the total yield of 1a
2
3
4
5
4c
4c
4g
4g
2c
2d
2b
2d
5h
5i
Me
Me
H
Me
H
Me
Me
Ph
–
90)
–
85)
83
–)
–
76)
–
(
(91:9)
–
(100:0)
100:0
(–)
(
Entry 3). The over-reduced product 7a was not obtained in this
case. In all cases, dienal (2E,4E)-1a was obtained, confirming the
2E,4E)-geometry of thioesters 5a–f. The reaction of strongly
(
5j
H
(
(
electron-withdrawing 4-nitrophenyl derivative 5e resulted in a
low yield of 1a (Entry 5). We speculate that coordination of the
carbonyl oxygen to the aluminum atom of DIBAL-H, which
triggers the reduction, is insufficient due to the low Lewis
basicity of 5e. Considering the results in Tables 1 and 2, good
crystallinity, and the commercial availability, p-chlorophenyl
thioesters were selected for further examination.
5k
H
H
Me
–
(
(100:0)
a
Yield of 5 obtained by crystallization. The data after column
chromatography of the crystallization residue are given in
parenthesis.
b
The 2E/2Z ratio of 5 obtained by crystallization. The data after
Table 2. DIBAL-H reduction of thioesters 5.
column chromatography of the crystallization residue are given in
parenthesis.
DIBAL-H reduction of dienyl thioester 5j under the
conditions shown in Table 2 gave the corresponding dienal 1b in
good yield (Scheme 3) [8].
Entr
y
5
Ar’
Yield 1a (%)a
2E/2Zb
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Ph
45 (31) [4]
– (67) [17]
47 (52) [0]
34 (51) [4]
12 (21) [13]
66 (28) [6]
99:1 (74:26)
– (77:30)
100:0 (88:12)
100:0 (93:7)
100:0 (81:19)
100:0 (82:18)
2 6 3
2,5-Me C H
Scheme 3. DIBAL-H reduction of dienyl thioester 5j to dienal
4-ClC
4-BrC
4-NO
4-MeOC
6
H
4
1
b.
6
H
4
The reaction sequence was further extended to the synthesis of
2
C
6
H
H
6 4
4
trienyl thioesters (Table 4). The TiCl -promotated condensation
4
between thioester 4g and dienals 1b–d [9] afforded trienyl
thioesters 6a–c, respectively (Entries 1–3). These products were
obtained by simple filtration due to their good crystallinity.
Although a commercially available, geometrical mixture of 2,4-
hexadienal (1d) (4E/4Z = 89:11) was used, a high E/Z ratio was
observed for crystallized product 6b (Entry 2). Brominated
product 6c would be synthetically useful because of
transformability of the alkenyl bromide moiety (Entry 3) [10]. In
fact, Suzuki-Miyaura coupling between thioester 6c and (E)-
a
Yield of 1a obtained by crystallization. The data after column
chromatography of the crystallization residue are given in
parenthesis. Yields of alcohol 7a are given in square brackets.
b
The 2E/2Z ratio of 1a obtained by crystallization. The data after
column chromatography of the crystallization residue are given in
parenthesis.
1
1
With S-4-chlorophenyl thioesters 4c (R = Me) or 4g (R = H),
the TiCl -aldol condensation with various -unsaturated
styrylboronic acid was effectively catalyzed by Pd(OAc)
2
/S-Phos
4
[
10e] to give tetraenyl thioester 8 without destroying the thioester
aldehydes were next investigated (Table 3). Like enal 2a,
cinnamaldehyde, tiglic aldehyde, and crotonaldehyde also
afforded the desired dienyl thioesters 5g–k in good yields with
high 2E/2Z ratios (Entries 1–5). The geometry of thioesters 5g–k
was determined by NOESY analysis or the coupling constants in
moiety (Scheme 4).
Table 4. Synthesis of trienyl thioesters 6.
1
H NMR analysis (see ESI).
4
Table 3. TiCl -promoted aldol condensation of thioester 4c or
4
g with various enals 2.
Entry
1
6
R
Yield (%)a
80 (–)
45 (18)
75 (–)
drb
1
2
3
1b
1c
1d
6a
6b
6c
Ph
Me
Br
100:0 (–)
97:3 (72:28)
100:0 (–)
a
Yield of 6 obtained by crystallization. The data after column
chromatography of the crystallization residue are given in
parenthesis.
Entry
1
4
2
5
R1
R2
H
R3
Ph
Yield
(
2E/2Zb
%)a
4c
2b
5g
Me
71
99:1 (–

4b
Tetrahedron
The ratio between (2E,4E,6E)-6 and the other isomers obtained
This work was supported by JSPS KAKENHI (grant numbers
6KT0164 and 19K06986). A. B. gives profound
by crystallization. The data after column chromatography of the
crystallization residue are given in parenthesis.
1
acknowledgement to MEXT for the scholarship sponsorship and
immense support during the research.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://...
References
[
[
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(
Scheme 4. Synthesis of tetraenyl thioester 8 via cross-
coupling between bromotrienyl thioester 6c and styrylboronic
acid.
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thioester 6a gave the corresponding trienal 9 in a good yield
(Scheme 5) [8].
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3] (a) M.F. Jacobsen, J.E. Moses, R.M. Adlington, J.E. Baldwin,
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8
835.
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Scheme 5. DIBAL-H reduction of trienyl thioester 6a to dienal 9.
The TiCl -promoted aldol condensation of -bromothioacetate
(
2001) 1959-1961. (b) R. Nagase, N. Matsumoto, K. Hosomi, T.
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4
(
4
h [11] with enal 2a proceeded well under the same conditions to
give -bromodienyl thioester 5l as crystals with high 2Z/2E ratio
Scheme 6). Reduction of 5l with excess DIBAL-H furnished
[
[
7] G.V. Kryshtal, G.M. Zhdankina, S.G. Zlotin, Eur. J. Org. Chem. (2005)
2822–2827.
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Zhdankina, N.V. Ignat’ev, M. Schulte, S.G. Zlotin, Tetrahedron 67
(
dienol (2Z/4E)-7b, which is a synthetic intermediate of aureothin
reported by Paolis and co-workers [4].
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[
[
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L. Duhamel, J. Chem. Soc., Perkin Trans. 1 (1997) 1639–1645.
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[
Scheme 6. Preparation of -bromo dienyl thioester 5l and
dienol 7b, a synthetic intermediate of aureothin.
Conclusion
It has been demonstrated from this work that dienyl or trienyl
thioesters can be synthesized via the one-pot TiCl -promoted
4
aldol condensations of S-aryl (especially S-4-chlorophenyl)
thioesters with enals or dienals. Due to good crystallinity,
products with high E/Z ratios were obtained by simple filtration
in many cases. Reduction of the thioester moiety by DIBAL-H
afforded the corresponding aldehydes while suppressing the E/Z-
isomerization and overreduction. The method was applied to
preparation of simple synthetic intermediates of natural products.
Further investigations to extend the synthetic utility are underway.
Acknowledgments

5
1
2
. One-pot synthesis of polyenyl thioesters
. Access to alkenyl bromides applicable to
coupling reactions
. Reduction of S-aryl thioesters to aldehydes with
less risk of over-reduction
. Application to preparation of synthetic
intermediates of polyene natural products
3
4