Synthesis of Strained γ-Lactams by Palladium(0)-Catalyzed C(sp3)-H Alkenylation and Application to Alkaloid Synthesis

Article abstract of DOI:10.1002/anie.201511457

A variety of strained α-alkylidene-γ-lactams were synthesized by palladium(0)-catalyzed intramolecular C(sp³)-H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for acce

Full text of DOI:10.1002/anie.201511457

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201511457
German Edition: DOI: 10.1002/ange.201511457
À
C H Activation
3
À
Synthesis of Strained g-Lactams by Palladium(0)-Catalyzed C(sp ) H
Alkenylation and Application to Alkaloid Synthesis
Philipp M. Holstein+, David Dailler+, Julien Vantourout+, Janah Shaya, Anthony Millet, and
Olivier Baudoin*
Abstract: A variety of strained a-alkylidene-g-lactams were
synthesized by palladium(0)-catalyzed intramolecular
3
À
C(sp ) H alkenylation from easily accessible acyclic and
monocyclic bromoalkene precursors. These lactams are val-
uable intermediates for accessing various classes of mono- and
bicylic alkaloids containing a pyrrolidine ring, as illustrated
with the synthesis of an advanced model of the marine natural
product plakoridine A and of the indolizidine alkaloid
d-coniceine.
T
he intramolecular palladium(0)-catalyzed activation of
3
À
non-acidic C(sp ) H bonds is a powerful tool for accessing
a vast array of bicyclic and polycyclic systems.[1–3] Recent
efforts in this field have focused on the use of non-aromatic
halogenated substrates, and allows synthesis of C(sp3)-rich
nitrogen heterocycles, which are of high interest for the
synthesis of active ingredients and natural products. In
particular, our group reported the construction of hexahy-
3
À
droindoles by intramolecular C(sp ) H alkenylation (Sche-
me 1a),[4a] and its application to the total synthesis of
aeruginosins.[4b,c] While the current work was in progress,
Cramer and co-workers disclosed the asymmetric synthesis of
b-lactams[5a] and cyclopropane-fused g-lactams (Sche-
me 1b)[5b] from a-chloroamides by intramolecular alkylation
3
À
Scheme 1. Palladium(0)-catalyzed intramolecular C(sp ) H alkenyla-
tion and alkylation to synthesize bicyclic and monocyclic N-hetero-
cycles.
3
À
of benzylic and cyclopropyl C(sp ) H bonds, respectively, in
the presence of a chiral ligand. Herein, we report a unique
example of an intramolecular alkenylation of unactivated
3
À
primary C(sp ) H bonds using acyclic bromoalkenes, thus
giving rise to mono- and bicyclic a-alkylidene-g-lactams
(Scheme 1c). This new method is relevant to the synthesis
of five-membered nitrogen heterocycles, which are present as
substructures in numerous bioactive natural products such as
pyrrolidine,[6a] pyrrolizidine,[6b] indolizidine,[6c] and Stemona[6d]
alkaloids.
three steps from 3,3-dimethylacrylic acid (Table 1). The main
problem was the formation of significant quantities of the
protodebrominated compound 3a, which is diagnostic of the
high ring strain created in such reactions.[2c,e, 4a] The first
interesting results were obtained with PPh2Et as the ligand, by
using reaction conditions similar to those initially developed
by Fagnou and co-workers (entry 1).[3f] Among the various
palladium sources tested, the allylpalladium(II) chloride
dimer turned out to be the best choice (entries 2 and 3).
Then, a number of trialkylphosphines and diphenylmonoal-
kylphosphines were screened (entries 4–9), and triphenyl-
phosphine emerged as the optimal ligand (entry 7). In
addition, cesium carbonate (1.5 equiv, optimized quantity)
was found to be the optimal stoichiometric base in combina-
tion with pivalic acid (entries 10 and 11). Furthermore, a high
reaction temperature of 1608C was found to be necessary,
since lower temperatures gave higher amounts of 3a
(entry 12). This result further illustrates the high activation
energy required to form the strained a-alkylidene-g-lactam
2a. Finally, the catalyst loading could be reduced to 5 mol%
palladium and 10 mol% ligand (entry 13), but the yield of 2a
We set out to optimize the cyclization of the SEM-
protected bromoamide 1a, which was readily synthesized in
[*] Dr. P. M. Holstein,[+] D. Dailler,[+] J. Vantourout,[+] J. Shaya,
Dr. A. Millet, Prof. Dr. O. Baudoin
UniversitØ Claude Bernard Lyon 1, CNRS UMR 5246, Institut de
Chimie et Biochimie MolØculaires et SupramolØculaires, CPE Lyon
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France)
D. Dailler,[+] Prof. Dr. O. Baudoin
Current address: University of Basel, Department of Chemistry
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: olivier.baudoin@unibas.ch
[+] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201511457.
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Table 1: Optimization of reaction conditions.
Entry Deviation from standard conditions
2a/3a[a] Yield
2a [%][a,b]
1
2
–
91:9
76:24
83
65
Pd(OAc)2 (10 mol%) instead of
[{Pd(h3-allyl)Cl}2]
3
Pd2dba3 (5 mol%) instead of
[{Pd(h3-allyl)Cl}2]
91:9
81
4
5
6
7
8
PCy3 instead of PPh2Et
PEt3 instead of PPh2Et
PPh2Me instead of PPh2Et
PPh3 instead of PPh2Et
P(p-NMe2C6H4)3 instead of PPh2Et
P(p-CF3C6H4)3 instead of PPh2Et
K2CO3 instead of Cs2CO3
Rb2CO3 instead of Cs2CO3
1408C instead of 1608C
47:53
41:59
84:16
91:9
86:14
–
83:17
86:14
46:54
22
35
78
83 (81)
49
0
64
76
20
9
10
11
12
13
14
2.5 mol% [{Pd(h3-allyl)Cl}2]/10 mol% PPh3 92:8
1.25 mol% [{Pd(h3-allyl)Cl}2]/5 mol% PPh3 84:16
91 (83)
79
[a] Determined by GCMS analysis of the crude reaction mixture.
[b] Determined by GCMS analysis using tetradecane as an internal
standard. Yield of isolated product 2a is given within parentheses.
SEM=[2-(trimethylsilyl)ethoxy]methyl, Piv=pivaloyl.
Scheme 2. Scope, limitations, and selectivity pattern of the intramolec-
3
decreased with lower catalyst loadings (entry 14). Under the
optimized reaction conditions, 2a was obtained in 83% yield
upon isolation, and the amount of 3a was less than 10% of the
À
ular C(sp ) H alkenylation reaction. [a] Reaction conditions: CF3CO2H,
anisole, 208C. [b] Obtained from enantiomerically pure substrates.
EOM=ethoxymethyl, TMB=2,4,6-trimethoxybenzyl.
mass balance (entry 13).
3
À
The scope and limitations of this intramolecular C(sp ) H
À
alkenylation reaction are shown in Scheme 2. First, the
nitrogen substituent was varied (Scheme 2a), and the reaction
was found to tolerate an aminal (2a,b) and trimethoxybenzyl
(2c) group,[5b] in addition to an alkyl (2e) group. Other amide-
protecting groups could either not be introduced or were
found to be unstable (for example, the Boc group; Boc = tert-
butyloxycarbonyl) to the current reaction conditions. Impor-
tantly, the TMB group in 2c could be cleaved under acidic
presence of less reactive methylene and methine C H bonds.
À
Indeed, the activation/cyclization of secondary C H bonds
À
was unsuccessful, even in the absence of primary C H bonds
À
(2m), except for more activated cyclopropyl C H bonds
(2l).[9] The reaction of bromoalkenes bearing a trisubstituted
double bond was also analyzed (Scheme 2c). Gratifyingly,
phenyl- (1n) and methyl-substituted (1p) Z-configured
bromoalkenes furnished the corresponding g-lactams with
similar efficiency. In contrast, the E isomer of 1n (1o) was
found to undergo rapid base-promoted elimination to give the
corresponding alkyne even in the absence of palladium
conditions to provide the NH-lactam 2d.[7]
2
À
The nature of the alkyl group (R ) undergoing C H
activation was varied (Scheme 2b) with R1 = SEM.[8] First, the
compound 1 f, containing a N-ethyl group (R2 = H) provided
only small amounts of the g-lactam 2 f along with the
corresponding protodebrominated product 3 f (2 f/3 f 14:86),
thereby demonstrating poor reactivity of linear alkyl groups.
In contrast, the reaction of the compound 1g, bearing a tert-
butyl substituent, was highly favored and gave rise to the g-
lactam 2g in 92% yield. The reactivity trend 1 f < 1a < 1g is
consistent with previous observations, and can be attributed
to Thorpe–Ingold effects, which have an important impact in
this class of reactions.[2f] Other substrates successfully under-
went selective activation/cyclization at primary (1h–j) and
À
catalyst, thereby precluding the C H alkenylation process.
The remarkable site-selectivity observed in the above
examples was further demonstrated with the reaction of the
compound 1q (Scheme 3), which provided the g-lactam 2q in
70% yield on a multigram scale. Among all potentially
reactive C H bonds in 1q, the primary C H bonds high-
lighted in Scheme 3 underwent cyclization selectively. The
lactam 2q can be viewed as an advanced intermediate for the
synthesis of the marine natural product plakoridine A,[10]
which is currently under study.
À
À
We next examined the selectivity of the activation of non-
À
À
cyclopropyl (1k) C H bonds to give the corresponding
monocyclic (2h–j) and spirocyclic (2k) g-lactams in the
equivalent primary C H bonds on the reactants 1r–u, which
may either give rise to the g-lactams 2r–u, or possibly to the
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yield (entry 1). Replacing the tert-butyl group with an
isopropyl group (1s) generated a separable mixture of both
lactam products (entry 2). In contrast, the substrate 1t,
derived from (À)-ephedrine and containing one methyl
group less than 1s, underwent selective reaction to form the
b-lactam 4t in moderate yield, and was accompanied by
significant amounts of the protodebrominated product 3t
(entry 3).
These results can be rationalized by considering the
opposing conformational and strain effects in the current
system (Scheme 4). The most stable conformation of the
Scheme 3. Gram-scale access to an advanced intermediate for the
synthesis of the marine product plakoridine A. TIPS=triisopropylsilyl.
more strained b-lactams 4r–u (Table 2). The compound 1r,
bearing N-methyl and N-tert-butyl substituents, underwent
selective reaction at the tert-butyl group to give 2r in high
À
Table 2: Selectivity of the activation of primary C H bonds.
Scheme 4. Contradictory effects on reaction selectivity. Bottom: DFT-
optimized structures (M06/6-31G**), H atoms omitted for clarity.
With these substituents, A was computed to be more stable than B by
4.8 kcalmolÀ1 and 2r more stable than 4r by 19.5 kcalmolÀ1
.
Entry
1
Reactant
Product(s)[a]
2/4[b]
palladium intermediate undergoing C H activation[2c,3f,h] is A,
where the smallest N-methyl substituent turns toward the
palladium center [see the computed model structure with X =
À
À
Pd(PMe3)OAc]. However, C H activation at this methyl
group and/or C C reductive elimination to form the b-lactam
À
1r
2r (92%)
4r (0%)
>98:2
4 should be disfavored because of the generation of ring
strain. In contrast, the formation of the less strained g-lactam
2 should be easier, but has to occur from the higher-energy
conformer B. Increasing the number of methyl groups at R1,
R2 should increase the population of this reactive conformer
B and should thus favor the g-lactam product (Table 2,
entries 3–1). Finally, the reactant 1u, bearing N-methyl and
N-cyclohexyl groups provided a separable mixture of 4u and
3u, together with traces of 2u, as expected from the lack of
2
3
1s
2s (38%)
2t (<5%)
2u (<5%)
4s (11%)
71:29[c]
À
reactivity of secondary C H bonds under the current reaction
conditions (Table2, entry 4; also see 2m in Scheme 2). These
results show that the formation of highly strained a-alkyli-
dene-b-lactams is also feasible upon careful choice of amide
substituents, but with reduced efficiency compared to
g-lactams.[11]
1t
4t (47%)
7:93[c]
4
À
The asymmetric C H alkenylation of 1a in the presence
of a chiral ligand instead of PPh3 was also studied. In
particular, we tested P-arylbinepines, chiral surrogates of
1u
4u (40%)
<2:98[c]
PPh3,[12b] as they were reported to provide high enantioselec-
[a] Yield of isolated product is given within parentheses. [b] Determined
by GCMS analysis of the crude reaction mixture. [c] The corresponding
protodebrominated products 3s–u were also formed in the following
ratios (GC): 2s/4s/3s 53:22:25; 2t/4t/3t 5:63:32; 4u/3u 48:52.
3
À
tivities in intramolecular C(sp ) H arylations leading to
(fused) indanes.[12,13] We found that the ligand L1, which
was initially introduced by Fu and co-workers,[14] led to g-
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À
5a,b underwent deoxybromination and reduction of the C Br
bond under classical conditions (Scheme 6b). Reduction of
the resulting saturated lactam with LiAlH4 and protonation
afforded racemic d-coniceine hydrochloride in good overall
yield.[16]
Finally, fused pyrrolidine 2x and azepane 2y, relevant to
the synthesis of pyrrolizidine[6b] and Stemona[6d] alkaloids,
respectively, were obtained in a similar fashion from easily
À
accessible precursors 1x,y by intramolecular C H alkenyla-
tion (Scheme 6a). However, compound 2x was obtained in
low yield due to competitive protodebromination (2x/3x 1:1)
which likely results from excessive ring strain in the formation
of the 5,5 ring system.[2e]
3
À
Scheme 5. Proof-of-concept enantioselective C(sp ) H alkenylation.
In conclusion, a variety of a-alkylidene-g-lactams were
3
À
lactam 2a with moderate enantioselectivity (Scheme 5).
Although there is admittedly room for improvement, this
obtained by palladium(0)-catalyzed intramolecular C(sp ) H
alkenylation of easily accessible acyclic bromoalkene precur-
sors. These lactams can be employed to access various classes
of mono- and bicylic alkaloids containing a pyrrolidine ring.
result constitutes a proof of concept for enantioselective
3
À
g-lactam synthesis through this C(sp ) H alkenylation
method.
Next, the reactivity of monocyclic precursors, relevant to
the synthesis of bicyclic alkaloids, was examined (Scheme 6a).
Acknowledgments
This work was financially supported by Minist›re de l’Edu-
cation Nationale, de l’Enseignement SupØrieur et de la
Recherche, RØgion Rhône-Alpes, Institut Universitaire de
France and the University of Basel.
À
À
Keywords: C C coupling · C H activation · natural products ·
nitrogen heterocycles · palladium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2805–2809
Angew. Chem. 2016, 128, 2855–2859
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yield. More strikingly, a piperidine precursor (1w) containing
À
a single exocyclic methyl group underwent selective C H
alkenylation, to give the fused g-lactam 2w in 71% yield on
a gram scale. No trace of product arising from activation at
À
the methylene C H bonds a to the nitrogen atom was
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À
[8] No sign of C H activation at the SEM group was ever observed
À
in the current study, despite the presence of C H bonds adjacent
to both nitrogen and oxygen atoms.
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À
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Received: December 10, 2015
Published online: January 21, 2016
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