Development and Elucidation of a Pd-Based Cyclization–Oxygenation Sequence for Natural Product Synthesis

Article abstract of DOI:10.1002/anie.201913730

Pd-catalyzed sequences involving oxidative addition, cyclization, and termination through intermolecular nucleophile capture have tremendous utility. Indeed, they can generate a plethora of different polycyclic structures possessing a diverse range of fun

Full text of DOI:10.1002/anie.201913730

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Accepted Article
Title: Development and Elucidation of a Pd-based Cyclization/
Oxygenation Sequence for Natural Product Synthesis
Authors: Heng Yi, Pengfei Hu, and Scott A Snyder
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10.1002/anie.201913730
Angewandte Chemie International Edition
COMMUNICATION
Development and Elucidation of a Pd-based Cyclization/
Oxygenation Sequence for Natural Product Synthesis
Heng Yi,+ Pengfei Hu,+ and Scott A. Snyder*[a]
Abstract: Pd-catalyzed sequences involving oxidative addition,
cyclization, and termination through intermolecular nucleophile
capture have tremendous utlity. Indeed, they can generate a
plethora of different polycyclic structures possessing a diverse range
of functionality. However, one area of deficiency for Pd(0)/Pd(II)
variants is the ability to conclude them with oxygen-based species.
Inspired by the recent discovery of one such reaction in the course
of a total synthesis program, we delineate herein that it has
significant power, both in terms of substrate scope as well as the
terminating oxygen nucleophile. As a result, the reaction proved
critical in achieving total syntheses of two oxygenated natural
products, one of which was prone to over-oxidation. Finally, a
mechanistic proposal that accounts for its success is provided.
obtained directly from 13 following an initial C–C bond
construction via migratory insertion, leading to similarly
situated quaternary center.[10]
Herein, we delineate the
development and scope of this overall reaction process, one that
is capable of affording a range of architectures with a variety of
a
terminating
oxygen-based
nucleophiles
with
complete
diastereocontrol. Critically, this method also provides general
access to the core carbon skeleton of the botrydial family of
natural products,[1b] with two members of this class successfully
synthesized in a concise fashion. In addition, mechanistic
studies provide a sound rationale for the sequence’s success.
AcO
H
Me
Me
Me
H
OH
OH
Me
H
O
O
Me
Me
Me
Me
Me
Among terpene-based natural products, there are a number
Me
O
O
of triquinanes and related congeners,[1] including (−)-
Me
2: botrydial
Me
presilphiperfolan-8-ol (1),[2] which possess
a
1,3-trans
1: (_)-presilphi-
perfolan-8-ol
3: botrydienal
stereochemical arrangement of substituents at the fusions of
their varied ring systems (colored here in blue). Given that
structural homology, our group has been interested in
developing a cohesive Pd-catalyzed cyclization approach to
fashion the diverse targets possessing such patterning. Our
previous work on the total synthesis of presilphiperfolan-8-ol
(1),[3] and other literature precedents,[4] have demonstrated that
the desired 1,3-trans selectivity could be achieved via a Pd-
mediated migratory insertion step (from 4 to 5). However,
further extensions of the process,[5] including an intermolecular
oxygen nucleophile terminating functionalization (5 to 6), are
needed to access molecules such as 2[6] and 3[7] that possess
an oxygen adjacent to the quaternary center.
X
X
X
HR
R
R
Pd(0)
[1,3-trans]
OR
Y
[function-
alization]
Z
Y
Y
Me
Me
PdII
OR
Me
4 [Z = OTf, Br, I]
5
6
Key methods of Pd-mediated oxo-functionalization of unactivated C(sp3)
DG
X
H
PdII
R2
PdIV
R2
OR
R2
Pd(II)
[O]
OR
or
[reductive
elimination]
R1
R1
R1
R1
R2
7
8
9
PdII
Nu
Pd (cat.)
ligand (cat.)
Z
Nu
While seemingly plausible, reports of C−O bond formation
from unactivated C(sp3)−Pd(II) intermediates are rare. Normally,
such processes occur via Pd(IV) intermediates (7→9),[8] typically
requiring the presence of an additional oxidant traditionally
incompatible with Pd(0)/Pd(II) catalytic systems. Nevertheless,
our hope was that the α-quaternary center in the alkyl-Pd(II)
intermediate 5 might enable its interception by an oxygen
nucleophile through intermolecular capture by precluding any
intramolecular reactions such as β-H elimination; such a strategy
has proven successful in promoting other types of challenging
reductive eliminations.[5e-n] In fact, we recently achieved one
example of such a functionalization as part of a total synthesis of
conidiogenol (16)[9] and related family members in which 14 was
10 (Z = Br, I, OTf)
11
12
Nu = H, C, B, N, Si, halogen…but not O
Me
Me
Me
Pd(OAc)2 (10 mol %),
t-BuMephos (15 mol %),
n-Bu4NOAc (3 equiv),
Me
Me
Me
H
H
H
H
toluene, 100 °C
OAc
OTf
13
Me
14 [isolable]
Me
(83%)
K2CO3, MeOH
Me
Me
Me
Me
Me
Me
H
H
H
H
OH
OH
[a]
H. Yi, P. Hu, Prof. Dr. S. A. Snyder
Department of Chemistry
University of Chicago
5735 S. Ellis Avenue, Chicago, IL, 60637 (USA)
E-mail: sasnyder@uchicago.edu
Me
OH
16: conidiogenol
Me
15
Scheme 1. Development of a unified approach to varied terpenes of different
oxidation states predicated on the development of a unique functionalization of
unactivated C(sp3)–PdII intermediates of type 5.
+
These authors contributed equally.
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.201913730
Angewandte Chemie International Edition
COMMUNICATION
Our investigations commenced using alkenyl triflate 17 as
the initial test substrate, searching for competent oxygen
nucleophiles and ligands in the presence of catalytic Pd(OAc)2.
As shown in Table 1, when Trixiephos[11] was used as the ligand
at a 30 mol % loading along with 10 mol % of Pd(OAc)2, only
trace product was obtained with NaOAc or KOAc as the oxygen
source (entries 1 and 2). By contrast, when the commercially
available and highly nucleophilic n-Bu4NOAc[12] was used, 18
was obtained in 61% yield based on NMR analysis (Entry 3).
Pleasingly, a decrease in the ligand loading to 15 mol % led to a
further increase in yield to 86% (Entry 4); any additional
attenuation in loading level resulted in lower conversion, as did
efforts to use less than 3.0 equivalents of n-Bu4NOAc. Further
ligand screening under these parameters ultimately revealed
that t-BuMephos[13] afforded the highest yield of 18 (95%, Entry
9). Finally, the reaction temperature could also be lowered to
90 °C with no erosion in material throughput (Entry 10).
tetrabutylammonium counterion worked as well to afford 32–36
smoothly in high yield.
Finally, investigations with non-
carboxylic acid-based nucleophiles revealed that phenols were
not competent unless the pKa of their acidic proton was in the
range of
a
typical carboxylic acid, as is true for
pentafluorophenol (pKa = 5.5 in H2O).[14] That salt afforded a 78%
yield of 37. 3,5-Ditrifluoromethylphenol (pKa = 8.26 in H2O),[15]
by contrast, did not lead to any desired product. A very modest
yield was observed using the salt of the acidic N-oxide HOBt in
the reaction leading to 38. Critical for all these successful cases
listed in Table 2 was that the salts (while easily prepared) had to
be scrupulously dry, an issue of import, as some proved to be
hygroscopic if not stored properly (see SI for detailed procedure).
Table 2. The scope of the oxygen nucleophile in the Pd-based cyclization.[a,b]
Me
Me
Me
Me
Pd(OAc)2 (10 mol %),
t-BuMephos (15 mol %),
n-Bu4NOR (3 equiv)
MeO2C
Me
MeO2C
Table 1. Condition screening for a Pd-based cyclization/functionalization.[a]
toluene, 90 °C, 5 h
OR
OTf
17
Me
Me
Me
Me
Me
19-38
Pd(OAc)2 (10 mol %),
ligand,
acetate source (3 equiv),
MeO2C
Me
MeO2C
19: R = H [80%]
20: R = 4-Me [79%]
21: R = 4-OMe [37%]
26: R = 4-CO2Me [74%]
27: R = 4-COPh [92%]
28: R = 4-Cl [70%][c]
29: R = 4-F [90%]
30: R = 3-F [80%]
31: R = 2-F [87%]
Me
Me
OTf
17
OAc
toluene
MeO2C
Me
18
22: R = 3-OMe [60%]
R
23: R = 4-CHO [89%]
24: R = 4-CN [78%]
25: R = 4-CF3 [97%]
O
Yield (%)[b]
Me
Me
Entry
Ligand (loading)
Acetate source
NaOAc
O
Me
Me
Me
Me
Me
Me
1
-
4
Trixiephos (30 mol %)
Trixiephos (30 mol %)
Trixiephos (30 mol %)
Trixiephos (15 mol %)
Johnphos (15 mol %)
t-BuDavephos (15 mol %)
t-BuXantphos (15 mol %)
dtbpf (15 mol %)
MeO2C
MeO2C
NPhth
MeO2C
2
KOAc
O
3
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
n-Bu4OAc
61
O
O
Me
Me
33 [87%]
O
O
O
4
86
34 [92%]
32 [88%]
Me
Me
Me
O
5
76
Me
MeO2C
MeO2C
6
82
O
O
7
52
Me
35 [76%]
Me
36 [60%]
Me
O
O
N
8
22
Me
9
95
t-BuMephos (15 mol %)
t-BuMephos (15 mol %)
Me
Me
MeO2C
MeO2C
10[c]
96 (95)
F
F
[a]
O
F
F
O
Reaction conditions unless otherwise noted: 17 (0.2 mmol), Pd(OAc)2 (0.02
N
N
Me
Me
mmol), ligand (0.03 mmol), acetate source (0.6 mmol), toluene (2 mL), 130 °C;
F
[b] Yields were determined via 1H NMR using 1,3,5-trimethoxybenzene as an
[c]
internal standard with the yield in parentheses reflecting an isolated yield;
37 [78%]
38 [9%]
[a]
Reaction conditions unless otherwise noted: 17 (0.1 mmol), Pd(OAc)2 (0.01
mmol), t-BuMephos (0.015 mol), acetate source (0.3 mmol), toluene (1 mL),
90 °C, 5 h; [b] Isolated yields; [c] Reaction temperature was 130 °C.
Reaction temperature was 90 °C.
Having identified this optimal condition set, we sought next to
explore the scope of compatible oxygen nucleophiles using
substrate 17 with a range of tetrabutylammonium salts. As
shown in Table 2, a wide variety of such salts formed from
benzoic acids with electron-donating and -withdrawing
substituents proved successful, irrespective of their overall
patterning, leading to the formation of products 19–31. In nearly
all cases the yields were high (>70%), although they were more
modest for the two most electron-rich analogs leading to 21 and
22. For salts with halogen substituents, only those that were not
prone to oxidative addition with Pd(0), such as –F and –Cl,
We next investigated the scope of the alkenyl triflate.
Gratifyingly, starting materials with different core skeletons
performed effectively under the optimal conditions using n-
Bu4NOAc as the terminating nucleophile to deliver a range of
fused bicyclic products in high yields and as single
diastereomers. Of note, the ring size of the starting alkenyl
triflate and the nature and position of substituents on the
periphery of that ring showed no impact on reactivity (39–41,
Table 3). Equally significant, a substrate with an oxygen linkage
between the alkenyl triflate and terminating olefin acceptor led to
a product (42) containing both an acetate group as well as an
proved competent.
Pleasingly, aliphatic acid salts with a
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10.1002/anie.201913730
Angewandte Chemie International Edition
COMMUNICATION
ether ring. And, pleasingly, an alkoxymethyl substituted olefin
precursor led to the asymmetric formation of a new quaternary
center in 43 in which the two oxygen centers were differentiated
by the acetate group installed from the reaction. Substrates
designed to undergo 6-exo-trig cyclization proved to be the most
challenging, as the yield for these events, illustrated here for
product 44, were consistently lower than for those formed
As a final demonstration of the power of the developed
reaction, we attempted to utilize it for the preparation of natural
products of types 2 and 3 (cf. Scheme 1). As shown in Scheme
3, we were able to access both botrydienal (3) as well as an
aromatized variant (58). Those efforts began with ketone 54,[3]
prepared in one step from (R)-pulegone.
Subsequent
conversion into 55 was achieved in a single pot by effecting
oxycarbonylation with Mander’s reagent[18] followed by alkenyl
triflate formation. With the stage now set for the key Pd-based
cyclization, we found that while the reaction proceeded
effectively using toluene (35% yield), a superior outcome was
obtained using EtOAc instead, with 56 formed as a single
diastereomer in 67% yield after 12 h. Subsequent hydrolysis
with 1.05 equivalents of K2CO3 in MeOH at 23 °C over the
course of 10 h afforded 57 in 60% yield; its oxidation with SeO2
in 1,4-dioxane at 110 °C then completed a 5 step synthesis of
the enantiomer of 10-oxodehydrodihydrobotrydial (58).[19]
Intriguingly, if 56 was treated with an excess of K2CO3 (10 equiv)
in MeOH under the same conditions, a free alcohol was
generated instead which could be smoothly protected as a TBS
ether. This specific protecting group proved essential to the
subsequent SeO2-mediated allylic oxidation,[20] as the original
acetate or its pivaloate, TIPS, or TMS-protected congeners
generally afforded aromatized materials and/or uncharacterized
side-products during that oxidation (including attempts with
through 5-exo-trig cyclizations.
If intramolecular β-hydride
elimination was possible, the reaction was unable to deliver
product in any useful yield; one example is provided in the
Supporting Information section.
Table 3. The scope of the alkenyl triflate in the Pd-based cyclization.[a]
X
X
Pd(OAc)2 (10 mol %),
t-BuMephos (15 mol %)
,
n-Bu4NOAc (3 equiv)
Y
Y
toluene, 90 °C, 5 h
OAc
OTf
Z
Z
Me
Me
Me
Me
Me
O
H
MeO2C
Me
Me
Me
OAc
OAc
OAc
Me
39 [96%]
Me
Me
Me
40 [86%]
Me
Me
41 [73%]
Me
Me
many other oxidants).
Finally, dehydration of that newly
Me
MeO2C
MeO2C
MeO2C
installed allylic alcohol with the Burgess reagent[21] and standard
protecting group and oxidation state changes completed the
enantioselective total synthesis of botrydienal (3) in 9 steps
overall.[22]
O
OAc
OAc
OAc
Me
42 [83%]
Me
44 [24%]
OBn
43 [68%]
[a] Reaction conditions unless otherwise noted: substrate (0.1 mmol), Pd(OAc)2
(0.01 mmol), t-BuMephos (0.015 mol), n-Bu4NOAc (0.3 mmol), toluene (1 mL),
90 °C, 5 h.
Me
Me
Me
Me
Me
Me
b) K2CO3,
MeOH
MeO2C
Me
MeO2C
O
OAc
(13%)
a) Pd(OAc)2,
t-BuMePhos,
n-Bu4NOAc
(95%)
OTf
D
O
D
Given that final set of results, and in an effort to study the
mechanism and deduce what parameters might be key for
success of the sequence, deuterium-labeled 45 was prepared
Me
Me
D
H
H
45
47 [determined by nOe]
46
[SN2]
and subjected to the standard reaction conditions.
This
[SN2']
Me
Me
Me
Me
transformation led to the formation of 46 in 95% yield as a single
diastereomer. As such, the formation of a single product
provided evidence that a radical mechanism was not at play. To
establish the relative stereochemistry of the deuterium-
containing carbon, 46 was subsequently treated with K2CO3 in
MeOH. That operation afforded lactone 47 in 13% yield along
with both recovered starting material and hydrolyzed, but non-
cyclized, material. Critically, nOe studies of 47 revealed that the
deuterium atom was trans to the methyl group, indicating that
the new C–O bond within 46 was formed via a stereoinvertive
process; therefore, either an SN2-type substitution on
intermediate 49 or an SN2’-type reaction with its equilibrium
congener cyclopropane 50 would be required for its formation.[16]
We believe the latter is more likely, with the generation of a
strained ring potentially being a critical element for the reactivity
needed for oxygen incorporation by giving the intermediate
enhanced reactive character.[17] Evidence for the existence of
cyclopropane intermediates was provided by substrate 51, with
functionalization of the intermediate π-allyl species (52) proving
to be more expedient than cyclopropane ring opening.
IID
Me
Me
MeO2C
MeO2C
Pd
PdII
H
Me
PdII
H
H
CO2Me
D
Me
Me
D
OAc
49
50
48
OAc
OAc
PdX
c) Pd(OAc)2,
t-BuMePhos,
n-Bu4NOAc
MeO2C
MeO2C
MeO2C
OTf
51
(56%)
Me
52
Me
Me
53
Scheme 2. Key mechanistic analysis of the process using deuterated
substrate 45. (a) Pd(OAc)2 (10 mol %), t-BuMephos (15 mol %), n-Bu4NOAc
(3.0 equiv), toluene, 90 °C, 5 h, 95%; (b) K2CO3 (5.0 equiv), MeOH, 12 h,
13%; (c) Pd(OAc)2 (10 mol %), t-BuMephos (15 mol %), n-Bu4NOAc (3.0
equiv), toluene, 90 °C, 5 h, 56%.
In conclusion, inspired by the homology of several natural
product architectures and aiming to develop a unified approach
to access their differentially functionalized variants, we were
able to develop a one-pot Pd-catalyzed cyclization/oxygenation
reaction featuring C−O bond formation from an unactivated
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10.1002/anie.201913730
Angewandte Chemie International Edition
COMMUNICATION
C(sp3)−Pd(II) intermediate in
Mechanistic studies have revealed this event to be
a Pd(0)/Pd(II) catalytic cycle.
Mr. Kenneth DeBacker for the preparation and purification of
some of the starting materials. Financial support for this work
came from the University of Chicago, the National Institutes of
Health (R01-GM132570) and Bristol-Myers Squibb (graduate
fellowship to P. H.).
a
stereoinvertive process, with reaction probes revealing wide
scope in substrate and nucleophile. Specific applications have
ultimately afforded short and enantioselective total syntheses of
two sesquiterpenes in the botrydial family. Further efforts to
extend this reaction process and apply it to other complex
molecules, as well as to develop additional means of terminating
functionalization, are the subject of current endeavors.
Keywords: catalysis • Pd • oxygenation • total synthesis •
triquinanes
[1]
[2]
For selected reviews, see: (a) G. Mehta, A. Srikrishna, Chem. Rev.
1997, 97, 671. (b) I. G. Collado, A. J. M. Sánchez, J. R. Hanson, Nat.
Prod. Rep. 2007, 24, 674.
Me
Me
a) LDA,
Mander's
reagent;
H
H
Me
Me
Me
Me
CO2Me
LDA, Tf2O
(79%)
O
OTf
For isolation, see: (a) F. Bohlmann, C. Zdero, J. Jakupovic, H.
Robinson, R. M. King, Phytochemistry, 1981, 20, 2239; (b) R. M.
Coates, Z. Ho, M. Klobus, S. R. Wilson. J. Am. Chem. Soc. 1996, 118,
9249. For a review discussing the biosynthesis and chemical synthesis
of the presilphiperfolanol family, in particular, see: (c) Hong, A. Y.;
Stoltz, B. M. Angew. Chem. Int. Ed. 2014, 53, 5248.
Me
Me
54
55
b) Pd(OAc)2,
t-BuMePhos,
n-Bu4NOAc
(67%)
[3]
[4]
P. Hu, S. A. Snyder, J. Am. Chem. Soc. 2017, 139, 5007.
Me
Me
(a) R. Grigg, J. M. Sansano, V. Santhakumar, V. Sridharan, R.
Thangavelanthum, M. Thornton-Pett, D. Wilson, Tetrahedron 1997, 53,
11803; (b) L. E. Overman, M. M. Abelman, D. J. Kucera, V. D. Tran, D.
J. Ricca, Pure Appl. Chem. 1992, 64, 1813.
H
H
Me
Me
c) K2CO3
Me
CO2Me
OTBS
CO2Me
OAc
Me
d) TBSCl
(77% overall)
Me
Me
56
[5]
For selected reviews on such reactions and subsequent
functionalizations, see: (a) E. Negishi, C. Copéret, S. Ma, S.-Y. Liou, F.
Liu, Chem. Rev. 1996, 96, 365; (b) R. Grigg, V. Sridharan, J.
Organomet. Chem. 1999, 576, 65; (c) D. A. Petrone, J. Ye, M. Lautens,
Chem. Rev. 2016, 116, 8003; (d) Y. Ping, Y. Li, J. Zhu, W. Kong,
Angew. Chem. Int. Ed. 2019, 58, 1562. For selected examples of
recent cyclization and functionalization chemistry, see: (e) B. Burns, R.
Grigg, V. Santhakumar, V. Sridharan, P. Steven, T. Worakun,
Tetrahedron 1992, 48, 7297; (f) S. G. Newman , M. Lautens J. Am.
Chem. Soc. 2011, 133, 1778; (g) H. Liu, C. Li, D. Qiu, X. Tong, J. Am.
Chem. Soc. 2011, 133, 6187; (h) C. Chen, L. Hou, M. Cheng, J. Su, X.
Tong, Angew. Chem. Int. Ed. 2015, 54, 3092; (i) H. Zheng, Y. Zhu, Y.
Shi, Angew. Chem. Int. Ed. 2014, 53, 11280; (j) W. Kong, Q. Wang, J.
Zhu, J. Am. Chem. Soc. 2015, 137, 16028; (k) W. Kong, Q. Wang, J.
Zhu, Angew. Chem. Int. Ed. 2016, 55, 9714; (l) Z. Jiang, L. Hou, C. Ni,
J. Chen, D. Wang, X. Tong, Chem. Commun. 2017, 53, 4270; (m) A.
Liu, X. Ji, B. Zhou, Z. Wu, Y. Zhang, Angew. Chem. Int. Ed. 2018, 57,
3233; (n) Y. Hosoya, I. Kobayashi, K. Mizoguchi, M. Nakada, Org. Lett.,
2019, 21, 8280.
59
e) SeO2
f) Burgess reagent
g) DIBAL-H; TBAF
(47%
overall)
i) K2CO3 (60%)
Me
Me
H
Me
OH
OH
O
Me
Me
Me
O
Me
60
Me
57
(29%)
(62% brsm)
h) Swern [O]
(45%)
j) SeO2
Me
Me
O
O
Me
Me
Me
Me
O
O
Me
Me
58: ent-10-oxodehydrodi-
3: botrydienal
hydrobotrydial
[6]
H.-W. Fehlhaber, R. Geipel, H.-J. Mercker, R. Tschesche, K. Welmar, F.
Schönbeck, Chem. Ber. 1974, 107, 1720.
Scheme
3. Total synthesis
of botrydienal (3) and
ent-10-
oxodehydrodihydrobotrydial (58) via the Pd-catalyzed cyclization cascade.
Reaction conditions: a) LDA (3.0 equiv), THF, -78 to 0 °C, 1.5 h, then HMPA
(3.0 equiv), Manders' reagent (3.3 equiv), THF, -78 °C, 1 h, then LDA (10
equiv), Tf2O (10 equiv), -78 °C, 4 h, 79%; b) Pd(OAc)2 (10 mol %), t-
BuMephos (15 mol %), n-Bu4NOAc (3.0 equiv), EtOAc, 90 °C, 12 h, 67%; c)
K2CO3 (10 equiv), MeOH, 23 °C, 10 h, 84%; d) TBSCl (1.5 equiv), imidazole
(1.6 equiv), DMF, 23 °C, 12 h, 92% e) SeO2 (4.0 equiv), 1,4-dioxane, 110 °C,
12 h, 49%, and 25% aromatization product; f) Burgess reagent (3.0 equiv),
toluene, 80 °C, 12 h, 96%; g) DIBAL-H (3.0 equiv), CH2Cl2, 0 °C, 1 h, then
TBAF (3.0 equiv), 3 h, 99%; h) (COCl)2 (20 equiv), DMSO (10 equiv), Et3N (30
equiv), CH2Cl2, -78 °C, 3 h, 45%; i) K2CO3 (1.05 equiv), MeOH, 23 °C, 10 h,
60%; j) SeO2 (4 equiv), 1,4-dioxane, 110 °C, 12 h, 29%, 62% b.r.s.m.
[7]
[8]
T. Kimata, M. Natsume, S. Marumo, Tetrahedron Lett. 1985, 26, 2097.
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Acknowledgements
[10] In perhaps the closest example to this process, the Mulzer group
reported a Pd-catalyzed cyclization and C−O bond formation reaction
on an advanced intermediate in their studies towards bielschowskysin.
However, they utilized ligand-free conditions significantly different from
We thank Dr. Antoni Jurkiewicz and Dr. C. Jin Qin for assistance
with NMR and mass spectrometry, respectively. We also thank
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10.1002/anie.201913730
Angewandte Chemie International Edition
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those reported here. In addition, their system tolerates halides, which
are not compatible in our reaction. The authors proposed a distinct
mechanism involving acetoxypalladation, cyclization, and β-Br
elimination processes, all as a Pd(II)-based system, not a Pd(0)/Pd(II)
cycle; however, it should be noted that since no mechanistic
experiments were performed, a pathway akin to that presented here
cannot be ruled out: M. Himmelbauer, J.-B. Farcet, J. Gapnepain, J. A.
Mulzer, Org. Lett. 2013, 15, 3098.
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[12] Intriguingly, the same oxygen source was the only one indicated as
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[22] For the only additional reported synthesis of members of the class
(targeting other compounds), see: C. Qiao, W. Zhang, J.-C. Han, W.-M.
Dai, C.-C. Li, Tetrahedron 2019, 75, 1739.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
H. Yi,+ P. Hu,+ S. A. Snyder*
Although Pd-based cyclizations are
of
tremendous
value,
certain
X
X
Page No. – Page No.
terminating functionalizations remain
challenging. Herein is described the
development of
oxygen-based reaction predicated on
a Pd(0)/Pd(II) catalytic cycle which
has wide substrate scope and works
with a range of acidic oxygen-based
Pd(OAc)2 (10 mol %),
t-BuMephos (15 mol %),
n-Bu4NOAc (3 equiv)
Development and Elucidation of a
Pd-based Cyclization/Oxygenation
Sequence for Natural Product
Synthesis
Y
a
terminating
Y
toluene, 90 °C, 5 h
OAc
OTf
Z
[27 examples]
[most >70% yield]
Z
Me
Me
additives.
Mechanistic studies
O
O
Me
Me
provide key details for the reaction’s
success, with its power enabling the
concise synthesis of two members of
the botrydienal family of natural
products.
Me
Me
O
O
Me
Me
botrydienal
ent-10-oxodehydro-
dihydrobotrydial
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