Research on Liebeskind-Srogl coupling/intramolecular Diels-Alder reaction cascade

Article abstract of DOI:10.1016/j.tetlet.2018.01.046

The Liebeskind-Srogl coupling/intramolecular Diels-Alder (IMDA) reaction cascade that stereoselectively affords a tricarbocyclic compound with a trans–trans-cis fused ring system including an all-carbon quaternary stereogenic center at the ring junction is described. The cascade reactions proceed quickly and stereoselectively afford the products within 2 h at room temperature in the presence of a suitable thioester. The developed protocol as well as the prepared chiral compounds are useful for the enantioselective total synthesis of terpenoids with the trans–trans-cis fused ring system.

Full text of DOI:10.1016/j.tetlet.2018.01.046

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Research on Liebeskind-Srogl coupling/intramolecular Diels-Alder
reaction cascade
⇑
Tomohiro Fujii, Yuta Oki, Masahisa Nakada
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Liebeskind-Srogl coupling/intramolecular Diels-Alder (IMDA) reaction cascade that stereoselectively
affords a tricarbocyclic compound with a trans–trans-cis fused ring system including an all-carbon qua-
ternary stereogenic center at the ring junction is described. The cascade reactions proceed quickly and
stereoselectively afford the products within 2 h at room temperature in the presence of a suitable thioe-
ster. The developed protocol as well as the prepared chiral compounds are useful for the enantioselective
total synthesis of terpenoids with the trans–trans-cis fused ring system.
Received 9 December 2017
Revised 9 January 2018
Accepted 18 January 2018
Available online xxxx
Keywords:
Ó 2018 Elsevier Ltd. All rights reserved.
Liebeskind-Srogl
Intramolecular
Diels-Alder
Cascade
Stereoselective
Diels-Alder reactions are important ring-forming reactions that
lead to the simultaneous formation of new bonds and stereogenic
centers. Indeed, the efficiency of these reactions has enabled the
synthesis of a number of natural products.1 In general, however,
Diels-Alder reactions accompanying the formation of all-carbon
quaternary stereogenic centers lead to low product yields because
of steric strain even in the presence of a Lewis acid or at elevated
temperatures.
Alkenes bearing electron-withdrawing groups are highly reac-
tive toward nucleophiles owing to their low LUMO energy level,
which facilitates Friedel-Crafts reactions and Diels-Alder reactions
with the concomitant formation of an all-carbon quaternary stere-
Preparation of alkenes bearing electron-withdrawing groups is
sometimes difficult because of their high reactivity. For example,
in the case of compound 3, which is a substrate for the intramolec-
ular Diels-Alder (IMDA) reaction to yield 4 (Scheme 1), the reactive
electron-deficient alkene undergoes undesired reactions during
the preparation of the substrate.
The IMDA reaction proceeds rapidly because of the diene teth-
ered with dienophile moieties; thus, it is beneficial for constructing
a polycyclic scaffold. Moreover, it would be a promising method for
constructing scaffolds of terpenoids when accompanied by the for-
mation of all-carbon quaternary stereogenic center. Nonetheless,
an all-carbon quaternary stereogenic center is generally difficult
to be formed by the IMDA reaction because it requires a high acti-
vation energy.
To overcome these obstacles, we decided to develop a formation
of a substrate/IMDA reaction cascade. We adopted Liebeskind-
Srogl coupling because it is a palladium-catalyzed reaction that
proceeds under neutral reaction conditions and is suitable for com-
pounds that are sensitive to acidic or basic reaction conditions.4 In
other words, we envisioned Liebeskind-Srogl coupling of a rela-
tively stable thiol ester 1 and alkenylstannane 2 would afford the
ogenic center. For example, a-alkylidene b-keto esters and imides
easily undergo cycloadditions, Friedel-Crafts reactions, and
Mukaiyama-Michael reactions. In addition, these carbonyl com-
pounds can act as bidentate ligands and coordinate to chiral metal
catalysts, thus facilitating carbon–carbon bond-forming reactions
via asymmetric catalysis.2 Reactions of alkenes bearing electron-
withdrawing groups along with the formation of an all-carbon
quaternary stereogenic center have been employed in natural pro-
duct synthesis. In our laboratory, the first enantioselective total
synthesis of bucidarasins has been accomplished via the highly
a-alkylidene b-keto ester 3, and the subsequent IMDA reaction
stereoselective Diels-Alder reaction of an
a-alkylidene b-keto
would furnish 4 (Scheme 1).
ester.3
We previously reported a highly stereoselective synthesis of 6
from 5.5 The chiral building block 6 would be useful for the total
syntheses of a variety of terpenoids (Scheme 2). Hence, when 6 is
converted to the corresponding
Liebeskind-Srogl coupling, the IMDA reaction would afford a
a-alkylidene b-keto ester via
⇑
Corresponding author.
E-mail address: mnakada@waseda.jp (M. Nakada).
https://doi.org/10.1016/j.tetlet.2018.01.046
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fujii T., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.046

2
T. Fujii et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Scheme 1. Liebeskind-Srogl coupling/IMDA reaction cascade.
Scheme 4. Preparation of 13–16 and structures of 17 and 18.
Scheme 2. Highly stereoselective Michael reduction/intramolecular Michael reac-
tion cascade.
12. Finally, condensation of 12 with thiols afforded thioesters
13–16. Thioesters 17 and 18 were prepared by the same method.6
Having prepared 13–18, we first examined the Liebeskind-Srogl
coupling/IMDA reaction cascade of 13–16 with alkenylstannane
19.8 We employed the standard reaction conditions for Liebe-
skind-Srogl coupling, as described in Table 1. The reactions of ethyl
and tert-butyl thioesters (13 and 14, entries 1 and 2, respectively)
with 19 did not give the desired products even at 50 °C, and the
starting materials were recovered. However, the reactions of phe-
nyl thioester 15 and 2-pyridyl thioester 16, which are known as
reactive thioesters, gave different results. The reaction of phenyl
thioester 15 under the same reaction conditions proceeded at room
temperature to afford the product as the single isomer in 58% yield
(entry 3). 2-Pyridyl thioester 16 reacted faster than phenyl thioe-
ster 15 to afford the product in 81% yield exclusively (entry 4). In
the above mentioned cascade reactions, b-keto ester 20 was not
detected on the TLC, indicating that the subsequent IMDA reactions
affording 21 proceeded quickly. Although we did not carried out
the reaction of 20 in the absence of the palladium or copper cata-
lyst, it cannot be denied that the used metal catalyst accelerated
the IMDA reaction of 20.
tricyclic product. This product would be used for the stereoselec-
tive construction of terpenoids such as atisanes and kauranoids,
which contain contiguous stereogenic centers including an all-car-
bon quaternary stereogenic center. Therefore, 6 was converted to
the corresponding thiol esters bearing a diene to examine the
Liebeskind-Srogl coupling/IMDA reaction cascade. We report
herein the details of the cascades that affords the products in a
highly stereoselective manner.
To examine the above cascade, we prepared diene substrates
bearing a thiol ester starting from 6. First, we attempted the Hor-
ner-Wittig and Julia-Kocienski reactions of 7 (Scheme 3), which
was derived from 6 via the reaction with benzenemethanethiol
(76%) and Fukuyama reduction (90%). However, these reactions
did not proceed, probably because of steric hindrance. However,
7 was successfully converted to iodoalkene 8 by the Takai reaction,
and subsequent Stille coupling afforded diene 9. Diene 106,7 was
prepared according to the same method.
We then examined the conversion of 9 to its thioesters
(Scheme 4). Direct conversion of 9 to the corresponding thioester
was unsuccessful. Interestingly, hydrolysis of 9 under a variety of
conditions did not afford the desired product 12, presumably due
to the low reactivity of 9 resulting from steric hindrance. Hence,
9 was reduced to the corresponding alcohol with LiAlH4, followed
by TPAP oxidation to afford 10; then Pinnick oxidation of 11 gave
Table 1
Liebeskind-Srogl coupling/IMDA reaction cascades of 13–16 with 19.
Entry
R1
Temp (°C)
Time (h)
Yield (%)a
1
2
3
4
Et (13)
rt to 50
rt to 50
rt
2–12
1–12
3
Trace
NR
tBu (14)
Ph (15)
2-Py (16)
58b
rt
0.5
81b
a
Isolated yield.
Single isomer.
b
Scheme 3. Preparation of diene 9 and structure of 10.
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T. Fujii et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
The relative configuration of the product 21, which possesses a
trans–trans-cis fused ring system, was elucidated as shown in
Table 1 which was supported by the NOE studies (Fig. 1).
NOESY studies of 24a (Fig. 3), a derivative of 24. The high
stereoselectivity could be well explained via the same transition
states as those depicted in Fig. 2. Note that 23 was not detected
on the TLC during the reaction, indicating that it was highly
reactive and its IMDA reaction proceeded quickly.
We also carried out the cascade reaction of 15 and 16 with 25
(E/Z = 1/4)9 (Table 3). The reaction of 15 with 25 stereoselectively
afforded 27, but the yield was low (31%, 27/isomer = 6:110 Table 3,
entry 1). To our surprise, the reaction of 16 did not afford the pro-
duct (Table 3, entry 2) and 16 could not be recovered. Intermediate
26 was not detected during the reaction in both cases. The struc-
ture of 27 (Table 3) was elucidated by NOESY studies of its deriva-
tive 27a (single isomer) (Fig. 4). The high stereoselectivity of the
reaction could be explained by the same transition states as those
in Fig. 2.
The stereoselectivity of the IMDA reaction of 20 could be
explained using the proposed transition states depicted in Fig. 2.
Two energetically favored transition states, TS1 and TS2, should
be considered in the IMDA reaction of 20. The conformation of
the two fused six-membered rings in TS1 is boat-boat, with a
methyl ester group at the pseudo axial position. Meanwhile, TS2
adopts a chair-boat conformation, with a methyl ester group at
the axial position, which suffers from 1,3-diaxial interaction.
Hence, TS1 was favored in this reaction, which explains the exclu-
sive stereoselectivity.
We then examined the cascade reaction with (E)-alkenyl stan-
nane 22 (E/Z = 20/1).2a Because phenyl thioester 15 and 2-pyridyl
thioester 16 underwent the Liebeskind-Srogl coupling, as
described above, their cascade reactions with 22 were examined
(Table 2). Both cascade reactions (Table 2, entries 1 and 2)
exclusively afforded 24 as the single isomer, but better reaction
yields were achieved when using 15 (Table 2, entry 1). These
results differ from those depicted in Table 1. 2-Pyridyl thioester
16 also reacted faster than 15 and disappeared after 0.5 h from
the start of the reaction, though an increase in the reaction time
did not improve the yield. These results could be attributed to
the fact that 16 is sensitive to the reaction conditions. The
relative configuration of 24 (Table 2) was determined based on
The cascade reactions of thioesters with alkenyl stannanes 22
and 25 afford
a-alkylidene b-keto esters bearing a substituent at
the terminal position of the dienophile moiety. Hence, we also
examined the cascade reactions of 17 and 18, which possess a
diene with a substituent at the terminal position (Table 4).
The reaction of phenyl thioester 17 with 19 afforded 29 as the
single isomer, but the yield was low (33% yield, Table 4, entry 1).
The yield was improved to 62% when 18 was used (entry 2). In
the above reactions, the coupling product 28 was not observed.
Fig. 3. NOE correlations found in the NOESY studies of 24a.
Fig. 1. NOE correlations found in the NOESY studies of 21.
Table 3
Liebeskind-Srogl coupling/IMDA reaction cascade of 15 and 16 with 25.
Fig. 2. Proposed transition states TS1 and TS2 for the IMDA reaction of 20.
Table 2
Liebeskind-Srogl coupling/IMDA reaction cascade of 15 and 16 with 22.
Entry
R1
Time (h)
Yield (%)a
1
2
Ph (15)
2-Py (16)
2
0.5
31b
Trace
a
Isolated yield.
b
Yield of an inseparable mixture of 27 and an unidentified isomer with a ratio of
6:1.
Entry
R1
Time (h)
Yield (%)a
1
2
Ph (15)
2-Py (16)
2
0.5
66b
44b
a
Isolated yield.
b
dr = >20/1 (by 1H NMR analysis).
Fig. 4. NOE correlations found in the NOESY studies of 27a.
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T. Fujii et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 4
Liebeskind-Srogl coupling/IMDA reaction cascade of 17 and 18 with 19.
Fig. 6. Structures of ent-21 and leukamenin E.
difficulty. Indeed, all the attempted cascade reactions stopped at
the first stage, and only the coupling product 30 was formed. The
desired product 31 was not obtained in the reactions (Table 5,
entries 1 and 2). The reaction of 17 gave 30 with higher yield
(entry1). Unfortunately, 30 did not undergo the IMDA reaction in
the presence of a Lewis acid or upon heating.
Entry
R2
Time (h)
Yield (%)a
In the reactions depicted in Tables 1–5, the Liebeskind-Srogle
coupling of 2-pyridyl thioesters 16 and 18 with alkenylstannane
19 bearing no substituent as well as the IMDA reactions of the cor-
responding products 20 and 28 were fast, and the final products
were formed in higher yields when compared to those of the reac-
tions of phenyl thioesters 15 and 17. On the other hand, 15 and 17
gave better results in the reactions with alkenylstannanes 22 and
25, which bear a substituent. The reason for this trend is not clear
at present, but the low yields in the reactions of 2-pyridyl thioe-
sters with sterically hindered alkenylstannanes 22 and 25 could
be due to the slow Liebeskind-Srogle couplings because reactive
thioesters were consumed during the coupling reactions via
unidentified processes and loss of more reactive 2-pyridyl thioe-
ster could be faster.
1
2
Ph (17)
2-Py (18)
10
2
33b
62b
a
Isolated yield.
Single isomer.
b
The structure of 29 was elucidated based on the NOESY studies of
29a, a derivative of 29 (Fig. 5). Hence, the stereoselectivity of the
above reactions could be explained by transition state models in
Fig. 2.
Next, we carried out the cascade reactions of 17 and 18 with 22
(Table 5). Since all the substrates and stannane bear a substituent,
large steric repulsion was expected in the transition states. Thus,
the reactions of 17 and 18 with 22 were expected to proceed with
In summary, we have developed the Liebeskind-Srogl coupling/
IMDA reaction cascade that stereoselectively affords a tricarbo-
cyclic compound with a trans–trans-cis fused ring system including
an all-carbon quaternary stereogenic center at the ring junction.
The cascade reactions proceed quickly and afford the products
within 2 h at room temperature in the presence of a suitable thioe-
ster. Thus, the 2-pyridyl thioester was suitable for reactions with
alkenylstannanes bearing no substituent at the b-position, and
the phenyl thioester was suitable for reactions with alkenylstan-
nane bearing a substituent at the b-position. The observed trends
can form the basis for further optimization of the reaction condi-
tions. Reactions of substrates bearing a substituent at the terminal
position of the diene with tri-substituted alkenylstannanes did not
undergo the cascade reaction and stopped at the first coupling
stage. These results indicate the limitations of the developed pro-
tocol in this study. However, the developed protocol as well as
the prepared chiral compounds are useful for the enantioselective
total synthesis of terpenoids with the trans–trans-cis fused ring
system such as leukamenin E,11 which includes the same tricyclic
scaffold as that of ent-21 (Fig. 6), so further investigations of the
cascade reaction is underway.
Fig. 5. NOE correlations found in the NOESY studies of 29a.
Table 5
Liebeskind-Srogl coupling/IMDA reaction cascade of 17 and 18 with 22.
Acknowledgments
We acknowledge supports of the Materials Characterization
Central Laboratory, Waseda University – Japan, for characterization
of new compounds. This work was financially supported in part by
the Grant-in-Aid for Scientific Research on Innovative Areas 2707
Middle molecular strategy from MEXT – Japan and a Waseda
University Grant for Special Research Projects.
Entry
R2
Time (h)
Yielda
30 (%)
31 (%)
1
2
Ph (17)
2-Py (18)
3
0.5
58b
53b
0
0
A. Supplementary data
a
Isolated yield.
b
The product was a mixture of geometrical isomers of the trisubstituted alkene
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.01.046.
moiety of 30.
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T. Fujii et al. / Tetrahedron Letters xxx (2018) xxx–xxx
5
(f) Nagatani K, Minami A, Tezuka H, Hoshino Y, Nakada M. Org Lett.
2017;19:810.
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