Catalytic Aza-Wacker Annulation: Tuning Mechanism by the Activation Mode of Amide and Enantioselective Syntheses of Melinonine-E and Strychnoxanthine

Article abstract of DOI:10.1021/acs.orglett.8b00725

An unprecedented N-substituent of the amide was found to be crucial for the successful annulation to establish 2-azabicyclo[3.3.1]nonane and other ring skeletons in good yield. The novel catalytic aza-Wacker annulation methodology was further illustrated

Full text of DOI:10.1021/acs.orglett.8b00725

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Aza-Wacker Annulation: Tuning Mechanism by the
Activation Mode of Amide and Enantioselective Syntheses of
Melinonine‑E and Strychnoxanthine
Changmin Xie,† Jisheng Luo,† Yuping Zhang,‡ Sha-Hua Huang,‡ Lili Zhu,† and Ran Hong*,†
†Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China
S
* Supporting Information
ABSTRACT: An unprecedented N-substituent of the amide was found to be crucial for the successful annulation to establish 2-
azabicyclo[3.3.1]nonane and other ring skeletons in good yield. The novel catalytic aza-Wacker annulation methodology was
further illustrated in the concise syntheses and the absolute configuration determinations of melinonine-E and strychnoxanthine.
studies on transition-metal-catalyzed hydroamination or aza-
Wacker-type reaction of alkenes.3 However, it was rather striking
to us that very limited examples associated with a bridged lactam
ring through aza-Heck cyclization have been reported. The
Bower and Watson groups realized the oxidative cleavage of the
N−O bond by optimal palladium(0) complexes and subsequent
cross addition to the pendant alkene to release a cyclized product
(Scheme 1).4 While the practicality of these aza-Heck conditions
remains uncertain, the annular variant of the aza-Wacker reaction
is largely underdeveloped despite substantial efforts having been
devoted to various N-containing mono and fused heterocycles.5,6
The bridged ring implementing unfavorable energetics might
retard the actual lactam formation, as the denoted cyclization in
Scheme 1 may require dramatic conformational alignment.
Moreover, the regioselectivity of the addition to the alkene
(proximal or distal) would result in different bridged rings. To
establish a proof of concept, cyclohexenyl amide 1 was designed
as a model substrate. One of the possible cyclization products, a
2-azabicyclo[3.3.1]nonane (morphan) skeleton derived from the
proximal addition, is abundant in natural products and a
privileged structure in drug development.7 The Larock protocol
(Pd(OAc)2 and NaOAc in DMSO)8 for aerobic Wacker
oxidation was adopted for the initial attempt due to its success
on the construction of the bridged lactone.
he construction of various N-containing bridged hetero-
Tcycles (e.g., morphine, gelsedilam, and peduncularine)
through C−N bond formation has been of prominent interest for
synthetic chemists to devise novel strategies and tactics (Scheme
1).1 In the context of our continued interest in developing
methods to address synthetic problems,2 we initially proposed
that a palladium-catalyzed cyclization via C−N bond formation
would easily construct a bridged lactam because the numerous
Scheme 1. Palladium-catalyzed construction of a bridged
lactam via C−N bond formation
The preliminary screening revealed that the substituent on the
amide N was crucial to proceed the requisite cyclization (Table
1).9 Only a N-sulfonylated amide gave the aza-Wacker product in
79% yield along with trace of double-bond isomer 3 (entry 3).
Further decreasing the catalyst loading, as the typical Larock’s
Received: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00725
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
aza-Wacker reaction, the profound effect via the addition of
HOAc might sustain the catalytic cycle with an intriguing
mechanism.13,14 The catalyst system was ratified by a gram scale
synthesis without detriment on the yield and selectivity (entry
17).
Table 1. Optimization of the aza-Wacker Cyclization
With the optimized conditions in hand, we first investigated
the substitution effect on the amide. A series of para-substituted
benzenesulfonamides (MeO, Me, H, and Cl) generally gave
excellent yields (2a−d) (Scheme 2). For the strong electron-
b
conditions cat.
(mol %)
conv.
(%)
1
yield (2)
c
entry
1
R
additive (equiv)
(%)
d
Bn
Pd(OAc)2 (20), NaOAc (2)
O2
<5
n.d.
2
OBn Pd(OAc)2 (20), NaOAc (2)
O2
49
<5
79
87
44
65
77
42
46
76
82
ab
,
Scheme 2. N-Substituents in the aza-Wacker Annulation
3
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Pd(OAc)2 (20), NaOAc (2)
O2
>99
92
4
Pd(OAc)2 (10), NaOAc (2)
O2
5
Pd(OAc)2 (5),
O2
NaOAc (2)
50
6
Pd(OAc)2 (10),
O2
>99
90
7
Pd(OAc)2 (10), LiOAc (2)
O2
8
Pd(OAc)2 (10), CsOAc (2)
O2
Pd(OAc)2 (10), tBuCO2Na (2)
O2
66
9
65
10
11
12
13
Pd(OAc)2 (10), NaOAc (2),
O2
86
e
BPY
Pd(OAc)2 (10), NaOAc (2),
O2
93
f
DAF
g
Pd(OAc)2 (5),
O2
NaOAc (2),
68
55
f
DAF
PdCl2(PPh3)2
(10), O2
NaOAc (1.5),
THF
<5
56
n.d.
21
a
b
1
Isolated yield of 2. The ratio (rr) of 2/3 was determined by H
c
d
h
NMR. The conversion was 82% after 6 h. Thirty mol % of Pd(OAc)2
for 6 h. Compounds 2i and 2j were confirmed by X-ray analysis; see
the SI. Ten mol % of Pd(OAc)2. A fused bicyclo compound 4 was
14
Pd(TFA)2 (10),
O2
e
f
15
16
Pd(OAc)2 (10), NaOAc/HOAc
O2
>99
>99
>99
89
(>25/1)
i
(1/1)
found for the N-Ts substrate; see the SI.
i
Pd(OAc)2 (5),
O2
HOAc (2)
92 (18/1)
91 (25/1)
j
i
17
Pd(OAc)2 (5),
O2
HOAc (2)
withdrawing group (p-NO2) in 1e, both the reaction rate and
selectivity decayed. A similar trend was also observed by Stahl in
aza-Wacker cyclization and may implicate the reversible nature of
C−N bond formation through a possible Pd-amidate complex.13
A principally more electron-rich sulfonyl group, MeSO2-(N),
also gave the desired product 2f in excellent yield (89%).
Interestingly, cyclization of the amide bearing N-OMe also
delivered lactam 2g in good yield (79%), albeit a slow rate under
higher catalyst loading. For amide 2h bearing the same functional
group as in Waston’s report,4b no annulation proceeded. Of note,
the catalyst system was also applicable for the construction of the
other ring systems (2i−k) in excellent yields under the optimal
conditions.
To gain further mechanistic insights into the amidopalladation
process, two stereochemically defined deuterated amides were
prepared and subjected to the aza-Wacker cyclization (Scheme
3).15 Under the optimal conditions, the N-Ts amide performed a
nucleophilic anti addition to the activated alkene by Pd species
and subsequent β-D cis-elimination to result in a cyclized product
2a as a major product (92%), while the deuterated 2a-d was only
8%. This scenario is consistent with previous mechanistic studies
on the aza-Wacker cyclization with the similar functionalized
amide.11,16 Interestingly, the cyclization of the N-OMe amide
would largely go through syn-amidopalladation to afford 2g-d in
a 83% D-incorporation (only 17% of the Hb signal was integrated
in the NMR spectra).15 Notwithstanding, further mechanistic
investigation is warranted to understand the profound effect of
the N substituent, this scenario would be advantageous for the
a
Reactions conditions: amide (0.1 mmol), catalyst (mol %), O2 (1
atm), additive (equiv), and 3 Å molecular sieves (30 mg) in DMSO (1
b
mL) at 100 °C. The conversion was determined by 1H NMR.
c
Isolated yield of 2 was given when the conversion was >99%; the
NMR yield for the rest of the entries was determined by 1H NMR with
d
e
internal standard, see the SI for details. n.d. = not determined. BPY
(6,6′-dimethyl-2,2′-bipyridine): 10 mol %. DAF (4,5-diazafluoren-9-
one): 10 mol %. 12 h. DMSO (2 equiv) as ligand, toluene (1 mL).
The ratio of 2/3 was determined by H NMR. One gram scale.
DMSO = dimethyl sulfoxide. Ts = 4-methylphenylsulfonyl.
f
g
h
i
j
1
condition,8c resulted in a dramatic detriment on the conversion
due to the rapid precipitate of Pd-black after 2 h (entry 5). In the
absence of NaOAc, the increase of the isomeric product 3
deteriorated the yield of 2 (ratio: 2/3 = 4/1) (entry 6).9 Other
metal acetates and a steric bulky carboxylate ion reduced both the
conversion and yield (entries 7−9). Although bipyridine-derived
ligands were reported to facilitate the aza-Wacker reaction under
several circumstances,10 in this study, these ligands were found to
be less efficient to promote the cyclization (entries 10−12).
Other palladium catalysts, which have been proven beneficial for
selected substrates,11,12 were less effective for the current process
(entries 13 and 14). The turning point commenced with the
addition of HOAc; both the reaction rate and the selectivity (2/
3) were amended (entry 15). The catalyst efficiency was further
improved when 2 equiv of HOAc was introduced (entry 16).
Given the denoted challenge for catalytic turnover in the aerobic
B
DOI: 10.1021/acs.orglett.8b00725
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
scale aza-Wacker reaction proceeded smoothly to deliver the
bridged compound 9 in 88% yield without affecting the acid-
labile silyl protecting group. Notably, in our initial attempt,
sulfonamide 8a was examined without notable success (9a in
21% yield),15 implicating that the antiamidopalladation of the N-
Ts amide is more sterically demanding toward the silylated alkyl
chain. After hydrogenation and facile cleavage of the N−O bond
by Kagan’s reagent (SmI2),22 the corresponding secondary amide
10 reacted with tryptophol tosylate 11 to give compound 12 in
91% yield. In contrast to previous reports,23 the classic conditions
(POCl3) applied to 12 only resulted in severe decomposition.
We reasoned that the labile silyl group was intolerable under
harsh conditions. A mild activation of the tertiary amide with
Tf2O/2,6-DTBP (2,6-ditert-butylpyridine)20,24 proved effective
in the cyclization to give product 13 in 95% yield. The X-ray
determination of the acetate derivative 14 also confirmed the
stereochemistry of the ring-formation step. The combination of
acetylation and subsequent exhaustive SeO2-mediated oxida-
tion23b yielded strychnoxanthine (chloride salt) ([α]D + 66.6 (c
1.18 in MeOH)). However, the cyclization of 12 and
dehydrogenation25 in “one-pot” delivered melinonine-E as a
yellow solid in 65% yield. The spectra of the synthetic
melinonine-E (chloride salt) was identical to the literature data
(chloride salt)17 and confirmed the absolute configuration of this
β-carbolinium alkaloid (synthetic: [α]D −11.1 (c 0.86 in
MeOH); natural: [α]D −13.9 (c 1.02 in MeOH)). The
stereochemical confirmation validated the biogenetic relevance
of melinonine-E and matadine.17,26 Moreover, the circular
dichroism (CD) spectrum of the synthetic strychnoxanthine
(chloride salt) showed a positive Cotton effect (Δε + 3.0) at 360
nm,15 which reconciles the reported data18 and thus can assign
the absolute configuration as (15R,17R,20R).
Scheme 3. Cyclization of Deuterated Amides and Proposed
Mechanism
a
a
The ratio in parentheses was determined by 1H NMR; the
coordinating ligands of palladium were omitted for clarity.
diverted synthesis of cyclized products by tuning the activation
mode of the amide.
Having accessed the aza-Wacker cyclization to construct
bridged lactams, our attention was drawn toward two morphan-
core-embedded alkaloids. Melinonine-E (5) was first isolated in
1957 by Bachli et al. from the bark of Strychnos melinoniana
̈
Baillon (Loganiaceae), a plant used as an African folk medicine
for the treatment of malaria.17 The plain structure was later
revised by Hesse et al. as a pentacyclic skeleton of a 2-
azabicyclo[3.3.1]nonane-fused β-carbolinium cation, which is
unprecedented in this category of alkaloids.18 Angenot et al. also
identified a biogenetically related structure (C14-oxo), strych-
noxanthine (6), from Strychnos gossweileri Exell (Loganiaceae).19
The uncertainty of the absolute configuration poses the question
whether these two structurally related alkaloids are indeed
biogenically correlated with other concomitant compounds.18
To streamline the synthesis, trans-lactone (−)-720 was reacted
with methoxylamine in the presence of trimethylaluminum21 and
immediate silylation to afford amide 8 (Scheme 4). A two gram
In summary, a unified approach to access 2-azabicyclo-
[3.3.1]nonane and other ring systems was realized by
palladium-catalyzed aza-Wacker cyclization for the first time.
The method described here is complementary to other synthetic
approaches to access various bridged lactams bearing tunable
alkene and carbonyl functionalities. The application was further
illustrated in the concise and enantioselective syntheses of
melinonine-E and strychnoxanthine in 5−6 steps from the
readily available chiral lactone 7. Through adjusting the
substituents on the amide N, the amidopalladation pathway
can be altered to realize the cyclization of synthetically valuable
substrates, which may inaugurate the incorporation of aza-
a
Scheme 4. Divergent Syntheses of Melinonine-E and Strychnoxanthine (Chloride Salts)
a
THF = tetrahydrofuran; TBSCl = tert-butyldimethylsilyl chloride; Tf2O = trifluoromethanesulfonic anhydride; brsm = based on the recovered
starting material.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00725.
Experimental procedures, spectroscopic data, and copies
of NMR spectra (PDF)
Accession Codes
CCDC 1500763 and 1814867−1814869 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
(6) (a) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111,
Corresponding Author
*E-mail: rhong@sioc.ac.cn.
ORCID
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2981. (b) Kocovsky, P.; Backvall, J.-E. Chem. - Eur. J. 2015, 21, 36.
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(c) Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Chem. Rev. 2018,
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Ran Hong: 0000-0002-7602-539X
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
36, 7749. (c) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson,
K. P. J. Org. Chem. 1996, 61, 3584. For a recent application of Wacker
reaction by Larock’s protocol in synthetic work, see: (d) Sparrow, K.;
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(9) For the extensive optimization of aza-Wacker cyclization, including
N-substituents, solvent, catalyst, additives, and temperature, see the
Supporting Information for details.
(10) White, P. B.; Jaworski, J. N.; Zhu, G. H.; Stahl, S. S. ACS Catal.
2016, 6, 3340.
(11) Lorion, M. M.; Duarte, F. J. S.; Calhorda, M. J.; Oble, J.; Poli, G.
Org. Lett. 2016, 18, 1020.
Financial support from the National Natural Science Foundation
of China (21672246 to R.H. and 21402121 to S.H.H.) and
Chinese Academy of Sciences (XDB20020100 and QYZDY-
SSWSLH026) are highly appreciated. We are grateful to Prof.
́ ̀
Luc Angenot (Universite de Liege) for providing us with an
authentic sample of natural strychnoxanthine and information
about the stereochemistry of this rare product. We also thank Jie
Sun (SIOC) for the X-ray analysis and Dr. Jie-Fei Cheng (OSRI)
for helpful discussions.
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