Palladium-Titanium Relay Catalysis Enables Switch from Alkoxide-π-Allyl to Dienolate Reactivity for Spiro-Heterocycle Synthesis

Article abstract of DOI:10.1002/anie.201804160

Reported herein is the divergent syntheses of [5,5] and [6,5] spiro-heterocycles under Lewis-acid-assisted palladium catalysis. In particular, an unprecedented switch from alkoxide-π-allyl to dienolate reactivity was achieved by the use of palladium-titanium relay catalysis, and represents umpolung reactivity of vinylethylene carbonates. This method uses a simple procedure and commercially available catalysts, and delivers both classes of spiro-heterocycles, bearing three contiguous stereocenters, in high yield and uniformly excellent diastereoselectivity.

Full text of DOI:10.1002/anie.201804160

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Accepted Article
Title: Pd-Titanium Relay Catalysis Enables Switch of Alkoxide-π-Allyl
to Dienolate Reactivity for Spiro-Heterocycle Synthesis
Authors: Yu Zhao, Li-Cheng Yang, Zher Yin Tan, Zi-Qiang Rong,
Ruoyang Liu, and Ya-Nong Wang
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Pd-Titanium Relay Catalysis Enables Switch of Alkoxide-π-Allyl to
Dienolate Reactivity for Spiro-Heterocycle Synthesis
Li-Cheng Yang, Zher Yin Tan, Zi-Qiang Rong, Ruoyang Liu, Ya-Nong Wang, and Yu Zhao
⃰
Abstract: We report herein divergent syntheses of [5,5] and [6,5]
spiro-heterocycles under Lewis acid-assisted palladium catalysis. In
particular, an unprecedented switch of alkoxide-π-allyl to dienolate
reactivity was achieved by the use of palladium-titanium relay
catalysis, which represents an umpolung reactivity of vinylethylene
carbonates. This catalytic method uses a simple procedure with
commercially available catalysts, and delivers both classes of spiro-
heterocycles bearing three continuous stereocenters in high yield
and uniformly excellent diastereoselectivity.
cycloaddition of VECs with various partners for five-membered
heterocycle synthesis.[4] Our group has realized the first use of
VECs as a five-atom synthon in the preparation of nine-
membered fused heterocycles.[5] Very recently, the Glorius
group also disclosed
a Pd-NHC co-catalyzed [5 + 2]
[
6]
cycloaddition of VECs in high stereoselectivity. Notably, all
these reported systems are based on the classical reactivity of
electrophilic Pd--allyl (plus nucleophilic alkoxide). We report
herein divergent syntheses of [5,5] and [6,5] spiro-heterocycles
using VECs with aurones under Lewis acid-assisted palladium
catalysis (Scheme 1b). In particular, an unprecedented
umpolung of VECs is achieved: intermediate I is converted to a
nucleophilic dienolate species with Pd-Ti relay catalysis, which
enables a highly diastereoselective [4 + 2] cycloaddition to
access [6,5] spirocycles (pathway B). It is noteworthy that during
the preparation of our manuscript, the Kleij group reported a
mechanistically related elegant example of self-coupling of
VECs through allylic alkylation of enolate.[7]
Spiro-heterocycles represent a highly valuable structural
motif in bioactive natural and synthetic compounds.[1] Two
classes of [6,5] and [5,5] spirocycles that show diverse biological
activities are exemplified in Figure 1. Despite the significant
recent advances in spiro-heterocycle synthesis,[2] the
development of new and efficient synthetic strategies to access
them with high stereo-control still represents an important goal in
organic synthesis. Catalytic methods that allow divergent
synthesis of skeletally diverse spirocycles, in particular, will be
highly desired.
Figure 1. Selected bioactive enties containing [6, 5]/[5,5] spirocyclic structures
Vinylethylene carbonates (VECs) have found much utility in
organic synthesis recently, with the -allyl species I formed via
decarboxylation serving as a common intermediate (Scheme 1a).
The Kleij group has developed a series of nucleophilic addition
to either the terminal or the internal position of -allyl I to deliver
valuable building blocks in high efficiency and stereoselectivity.[3]
Alternatively, the Zhang group has reported highly efficient [3 + 2]
[]
Dr. L.-C. Yang, Z. Y. Tan, Dr. Z.-Q. Rong, R. Liu, Y.-N. Wang and
Prof. Y. Zhao
Department of Chemistry, National University of Singapore
3
Science Drive 3, Singapore 117543
Scheme 1. Comparison of reactivities of VECs
E-mail: zhaoyu@nus.edu.sg
Homepage: zhaoyugroup.sg
Supporting information for this article is given via a link at the end of
the document.
Aurone 1a[8] and the corresponding imines[9] have found
much use in stereoselective cycloadditions in the past few years.
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Various benzofuran-fused heterocycles were prepared in this
way, which is a common structural motif in a large number of
bioactive compounds.[10] Based on our previous synthesis of
nine-membered heterocycles,[5] we hypothesized that the switch
of bulky tosyl-protected imine to enone 1a might enable an
attack of the alkoxide to the internal position of the Pd--allyl in
the final cyclization step for the synthesis of seven-membered
heterocycle 3 (Table 1). Despite much experimentation by
modifying the Pd-catalyzed procedure, no formation of 3 was
observed. One representative set of condition is exemplified in
entry 1.
synthesis, the excellent diastereoselectivity for three continuous
stereogenic centers is also noteworthy.
With the optimized reaction conditions in hand, we first
explored the scope of [3 + 2] cycloaddition (Scheme 2). To our
delight, excellent diastereoselectivity (>20:1) was observed for
all the substrates examined. For the variation on enone 1,
different electron-donating or electron-withdrawing substituents
at either para- or ortho-position on the aryl group were well
tolerated to yield 4a-4f in high yield (80-99%). Naphthyl-
substituted product 4g as well as furyl-substituted 4h were also
obtained in good yield of 73-86%. The scope for the substituted
VECs turned out to be broad as well. Different substituted aryl
groups were tolerated as shown in 4i-4l, similarly furyl-
containing 4m as well as cyclohexyl-containing 4n were
accessible using this methodology in excellent dr. The relative
configuration of 4m was unambiguously assigned by single
crystal X-ray analysis.
Table 1. Discovery and optimization of [4 + 2] and [3 + 2] cycloadditionsa
entry
ligand
dppbz
dppbz
dppbz
dppbz
dppbz
dppbz
dppbz
dppbz
SPhos
SPhos
dppbz
additive
\
product
yield (%)b
<2
drc
1
2
3
4
5
6
7
8
9d
\
\
\
Sc(OTf)
3
<2
\
i
Al(OPr)
3
\
<2
\
\
ZnF
2
4
\
<2
TiCl
\
<2
\
Mg(OTf)
2
\
<2
\
Mg(OEt)
2
4a
4a
4a
4a
5a
28
>20:1
>20:1
>20:1
>20:1
>20:1
t
Mg(O Bu)
2
2
35
t
Mg(O Bu)
69
0d,e
Mg(O Bu)
t
99
1
1
2
i
1
Ti(O Pr)
4
99
aThe reaction was carried out by using 2 equiv. of 2a (vs. 1a) and 5 mol%
catalyst at 24 °C. bIsolated yield. cDetermined by NMR analysis of the crude
aSee Table 1 and SI for details.
reaction mixture. d10 mol% SPhos. THF as the solvent.
e
Scheme 2. Scope of [3 + 2] cycloadditiona
At this stage, we decided to test the effect of Lewis acid co-
catalyst to activate enone 1a. Out of various trials (entries 2-7),
the use of Mg(OEt)
2
finally led to appreciable conversion, but to
We then turned our attention to the formation of [6,5]
spirocycle 5. A wider range of substrates bearing different
functionalities were examined (Scheme 3). Again, uniformly
excellent dr of >20:1 was obtained for all the spirocycle
formation. For enone 1, electron-donating groups such as
methoxy, dimethylamino and electron-withdrawing groups such
the alternative [5,5] spiro-heterocycle 4a instead in >20:1 dr. The
formation of five-membered ring is likely favoured due to kinetic
preference over the seven-membered product. As 4a represents
a key structural backbone in many bioactive compounds, efforts
were then invested to optimize this transformation. By screening
Mg-based Lewis acids, ligands for palladium and reaction media, as Cl, F on the aryl ring and the more bulky naphthyl unit were
we were able to achieve the formation of 4a in quantitative yield
all well tolerated (90-99% yield for 5a-5j). Enones with a furyl or
styrenyl substituents also underwent the cycloaddition smoothly
(5k-5l). To our gratification, other heterocycle-based enone
substrates also participated in this reaction to deliver 5m-5o,
albeit with lower yield. Various substituents on VECs were also
tolerated, including alkyl ones, to produce 5p-5v in high yields.
The relative configuration of this series of products was further
confirmed by X-ray analysis of single crystals of 5a and 5n. The
non-substituted VEC (R = H) was also examined, which
unfortunately underwent decomposition under the standard
conditions with no desired product formation.
t
with >20:1 dr by using Mg(O Bu)
2
and SPhos in THF (entry 10).
As a serendipitous discovery, an intriguing switch of reactivity
i
was observed when we examined the use of Ti(OPr)
4
(entry 11).
An unexpected [6,5] spiro-heterocycle 5a was obtained in
quantitative yield as a single diastereomer. The structure of 5a
corresponds to the backbone of many bioactive compounds.
More importantly, the formation of 5a clearly follows an
unprecedented mechanism with a reverse of polarity of VEC.
For the first time, VEC served as a four-atom synthon in
cycloaddition. In both series of [5,5] and [6,5] spirocycle
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COMMUNICATION
generated from Pd--allyl I, which then either reacts with 1a in a
formal [4 + 2] cycloaddition or undergoes protonation to yield
enone 6.
Table 2. Control reactions for [4+2] cycloadditiona
entry
variation from standard conditions
w/o 1a
yield of 5a
yield of 6
>95%
>95%
\
1
2
3
4
5
6
7
\
1a added after 18 h
6 instead of 2a
<2%
<2%
<2%
<2%
<2%
\
w/o Pd
2
(dba)
3
•CHCl
3
<2%
<2%
<2%
trace
w/o dppbz
i
w/o Ti(OPr)
4
t
w/o 1a; Mg(O Bu)
2
instead of
i
Ti(OPr)
4
aSee Table 1.
Our attempt of an enantioselective variant of this
transformation provided additional, important clue for the
reaction mechanism. As shown by some representative results
in Table 3, the use of chiral phosphine ligands including
bidentate and monodentate ones produced the desired product
in excellent yield and diastereoselectivity, but product 5a was
obtained in a racemic form in all cases (entries 1-2). This
suggested that the palladium-chelated species is likely not
involved in the enantio-determining step. In contrast, when we
switched to the use of chiral diols such as TADDOL as the
ligand for titanium, 5a was obtained with a significant 60% ee as
a single diastereomer (entry 3). This provided support for the
intermediate of a titanium species, likely a titanium dienolate,
which reacts with 1a in the stereo-determining cycloaddition step.
Scheme 3. Scope of [4 + 2] cycloadditiona
As the formation of 5 represents a new mechanism for VECs,
we carried out a series of control experiment to shed some light
on the reaction pathway. Under the standard conditions for 5
formation, a significant side product was observed, which was
identified to be the conjugate enal 6 (Table 2). This side product
is clearly formed from the excess VEC used in our reactions.
Consistent with that, when the reaction was carried out in the
absence of 1a, a complete conversion of 2a to 6 was observed
Table 3. Attempts of enantioselective [4+ 2] cycloadditiona
(
entry 1, Table 2). It is noteworthy that the formation of the
related enal was also reported by the Kleij group in their recent
work on self-coupling of VECs.[7] The formation of 6 was
confirmed to be an off-catalytic cycle side product, as the
addition of 1a after the formation of 6 (entry 2) or simply using 6
instead of 2a (entry 3) led to no conversion to 5a at all.
entry
ligand
additive
yield (%)b
drc
ee (%)d
Different components of the catalytic system were tested
next. Not surprisingly, no conversion was observed at all in the
absence of Pd salt/ligand (entries 4-5), supporting the
involvement of Pd--allyl I as a key intermediate. Intriguingly, no
conversion to either 5a or 6 was observed in the absence of
1
2
(R)-BINAP
\
99
99
87
>20:1
>20:1
<2
<2
60
(R)-MOPe
\
3
dppbz
(-)-TADDOLf
>20:1
i
t
a-c
See Table 1. Determined by chiral HPLC. e10 mol% loading. 40 mol%.
d
f
Ti(OPr)
4
(entry 6). When Mg(O Bu)
2
was used instead of
i
Ti(OPr)
4
in the absence of 1a, only trace amount of 6 was
The generation of dienolate from 6 under basic conditions
(stoichiometric lithium bis(trimethylsilyl)amide was used)
followed by reaction with 1a was also attempted. As shown in
Scheme 4, the desired product 5a could be obtained in
moderate yield and dr. Compared to the classical conditions, our
catalytic method provides an alternative and convenient base-
observed (entry 7). In situ NMR studies also showed the
t
formation of 6 was much slower with Mg(O Bu)
2
instead of
i
Ti(OPr)
4
(see Fig. S1 in SI). These evidence suggested that the
i
use of Ti(OPr) led to modification of the Pd--allyl to follow an
4
alternative pathway leading to the syntheses of 5a and 6. Based
on the structures of these two products, we propose the
involvement of a dienolate intermediate. This dienolate is
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free procedure for the production of 5a in high efficiency and
selectivity, despite the necessity to use two metal catalysts.
and [5,5] spiro-heterocycles are obtained in excellent yield and
i
diastereoselectivity. By the use of Ti(O Pr)
4
as the Lewis acid, in
particular, an unprecedented reverse of polarity for VECs is
realized to enable titanium-dienolate chemistry. The application
of this catalytically generated substituted dienolate to other
transformations is currently underway.
Acknowledgements
Scheme 4. Generation and reaction of dienolate under basic conditions.
We are grateful for the financial support from the Ministry of
Education of Singapore (R-143-000-613-112) and A*STAR
SERC (R-143-000-648-305).
Based on all the evidence in hand, we propose the
mechanism for the [4 + 2] cycloaddition in Scheme 5, which
features Pd-Ti relay catalysis. The Pd--allyl intermediate I is
formed from 2a and Pd(0).[11] On the one hand, I could undergo
standard [3 + 2] cycloaddition with the electrophilic 1a (using
Keywords: spirocycle • cycloaddition • umpolung reactivity •
relay catalysis • divergent synthesis
Mg-Lewis acid) to produce 4a. On the other hand, I may react
[1]
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Rep. 2010, 27, 1117–1137; b) A. Bartoli, F. Rodier, L. Commeiras, J.-L.
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i
with Ti(OPr)
4
to form an alternative intermediate II, in which
ligand exchange between Ti and Pd is proposed to free up the
alkoxide-Pd coordination and enable β-hydride elimination to
produce Ti-dienolate III. The Pd-hydride isopropoxide complex
released from this step then undergoes reductive elimination to
complete the Pd-catalytic cycle. In the titanium-catalytic cycle,
the formation of III converts the electrophilic Pd--allyl to a
nucleophilic Ti-dienolate. Substrate 1a is also likely activated by
the Ti-based Lewis acid, which undergoes reaction with III in a
formal vinylogous Michael addition. The resultant intermediate
IV undergoes intramolecular aldol followed by protonation to
yield the desired product 5a. In the presence of a chiral Ti-
complex, the formation of IV may proceed in an enantioselective
fashion as supported by data in entry 3, Table 3.
[
2]
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́
1
6
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Lett. 2017, 19, 6096−6099; f) J. Xie, W. Guo, A. Cai, E. C. Escudero-
Adan, A. W. Kleij, Org. Lett. 2017, 19, 6388−6391. For another example,
́
see: g) A. Khan, S. Khan, I. Khan, C. Zhao, Y. Mao, Y. Chen, Y. J.
Zhang, J. Am. Chem. Soc. 2017, 139, 10733–10741.
[
4]
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In summary, we have discovered a highly efficient and
divergent cycloaddition between enones 1 and VECs 2 under
cooperative Pd-Lewis acid catalysis. A range of valuable [6,5]
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[11] The use of vinyl epoxide analogous to 2a under standard conditions
could also yield 4 or 5 (albeit in lower yield of 72-80%), supporting the
formation of intermediate I.
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Li-Cheng Yang, Zher Yin Tan, Zi-Qiang
Rong, Ruoyang Liu, Ya-Nong Wang,
and Yu Zhao
⃰
Page No. – Page No.
We report herein divergent syntheses of [5,5] and [6,5] spiro-heterocycles under
Lewis acid-assisted palladium catalysis. In particular, an unprecedented switch of
alkoxide-π-allyl to dienolate reactivity was achieved by the use of palladium-
titanium relay catalysis, which represents an umpolung reactivity of vinylethylene
carbonates. This catalytic method uses a simple procedure with commercially
available catalysts, and delivers both classes of spiro-heterocycles bearing three
continuous stereocenters in high yield and uniformly excellent diastereoselectivity.
Pd-Titanium Relay Catalysis Enables
Switch of Alkoxide-π-Allyl to Dienolate
Reactivity for Spiro-Heterocycle
Synthesis
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