Enantio- and diastereoselective palladium catalysed arylative and vinylative allene carbocyclisation cascades

Article abstract of DOI:10.1039/c3cc42079e

The enantioselective synthesis of heavily decorated spirolactams has been accomplished via an arylative or vinylative allene carbocyclisation cascade. Mediated by silver phosphate, a range of allene-linked pro-nucleophiles and aryl or vinyl iodides were reacted in the presence of catalytic Pd(OAc)₂ and chiral bis(oxazoline) ligands to afford the spirolactam products in good yields and high enantio- and diastereoselectivities. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc42079e

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Enantio- and diastereoselective palladium catalysed
arylative and vinylative allene carbocyclisation
cascades†
Meiling Li,a Alison Hawkins,a David M. Barber,a Patrick Bultinck,b
Wouter Herreboutc and Darren J. Dixon*a
Cite this: Chem. Commun., 2013,
49, 5265
Received 21st March 2013,
Accepted 19th April 2013
DOI: 10.1039/c3cc42079e
www.rsc.org/chemcomm
The enantioselective synthesis of heavily decorated spirolactams
has been accomplished via an arylative or vinylative allene carbo-
cyclisation cascade. Mediated by silver phosphate, a range of
allene-linked pro-nucleophiles and aryl or vinyl iodides were
reacted in the presence of catalytic Pd(OAc)2 and chiral bis-
(oxazoline) ligands to afford the spirolactam products in good
yields and high enantio- and diastereoselectivities.
Scheme 1 Proposed Pd(0) catalysed enantioselective arylative allene carbo-
cyclisation cascade.
Cascade reaction processes, whereby simple starting materials
combine in a series of carbon–carbon or carbon–heteroatom
bond forming events, provide a resource efficient way of
generating complex, three dimensional molecular structures.1 describe our preliminary results leading to the first enantio-
When bond formation is enabled by the action of a catalyst, the selective palladium catalysed arylative allene carbocyclisation
nature and structure of any ligating groups, as well as other cascade.
parameters, can govern the relative and absolute configuration
The readily prepared allene-linked ketoamide 1a was
of the desired product.2 In this vein, we recently described an selected as a representative pro-nucleophile for our preliminary
efficient cascade process to access biologically relevant azaspiro- asymmetric carbocyclisation studies with methyl 4-iodobenzoate
cyclic structures3 via a palladium catalysed diastereoselective as the aryl halide coupling partner (Table 1). Our previously
arylative carbocyclisation of pro-nucleophile-linked allenes4 reported conditions were used to test substrate reactivity and
with aryl halides. With its many points of diversity and breadth generate the racemic product.5 Thus, reacting 1a and methyl
in scope, this cascade reaction was useful for library generation.5 4-iodobenzoate with Pd2(dba)3 (5 mol%), dppe (10 mol%) and
However, in the absence of any chiral controller the azaspiro- K2CO3 (2 equiv.) in DMSO at 70 1C for 8 hours, afforded
cyclic products were obtained as racemic mixtures. As part of a spirolactam 2a in 14 : 1 dr and 65% yield. Initial attempts to
broader program of work in our group targeting polycyclic induce asymmetry used similar conditions, but in place of
alkaloid natural products6 we recognised that an enantio- Pd2(dba)3 and the achiral bisphosphine ligand dppe, Pd(OAc)2
selective variant of this complexity building reaction was highly and the (S)-phenylalanine-derived (S,S)-bis(oxazoline) ligand 3f
desirable (Scheme 1). To date there have been only a handful of (Fig. 1) were used instead.10 Under these conditions, product 2a
reports on the catalytic enantioselective coupling reactions of was obtained in 65% yield with 18 : 1 dr, but unfortunately
allenes with organic halides to afford enantioenriched cyclic no enantiocontrol was observed (Table 1, entry 1). It has
products.7–9 Inspired by these findings, herein we wish to previously been demonstrated that in the presence of silver
salts significantly enhanced levels of asymmetric induction can
be achieved in ligand-controlled catalytic asymmetric coupling
reactions of allenes with aryl or vinyl iodides.8,9,11 Accordingly,
the reaction conditions were modified to include a basic silver
salt. Thus, K2CO3 was replaced with Ag3PO4 (0.5 equiv.) and
pleasingly significantly enhanced levels of enantioselectivity
were witnessed; 2a was obtained in 77% yield with 27 : 1 dr
and 59% ee (Table 1, entry 2). Variation of the solvent had a
pronounced effect on the enantioselectivity. Less polar solvent
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: darren.dixon@chem.ox.ac.uk
b Department of Inorganic and Physical Chemistry, Ghent University,
Krijgslaan 281-S3, 9000 Gent, Belgium
c Department of Chemistry, University of Antwerp, Groenenborgerlaan 171,
2020 Antwerp, Belgium
† Electronic supplementary information (ESI) available: Synthetic procedures,
experimental data, 1H NMR spectra, 13C NMR spectra, HPLC traces and VCD data
are available. See DOI: 10.1039/c3cc42079e
c
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Table 1 Optimisation studies using allene-linked indanone ketoamide 1a and
Table 2 Scope of the carbocyclisation of indanone ketoamide 1a with aryl
methyl 4-iodobenzoate
iodides and vinyl iodides
Entry R1 (aryl or vinyl)
2
Time (h) Yielda (%) drb eec (%)
1
2
3
4
5
6
7
8
Ph
2b 96
2c 48
2d 60
2e 48
2f 84
2g 72
2h 40
2i 72
2j 36
2k 72
82
85
76
86
79
84
77
70
61
72
67
78
77
68
70
65
45 : 1 87
56 : 1 87
39 : 1 89
41 : 1 86
25 : 1 86
33 : 1 87
35 : 1 86
40 : 1 75
21 : 1 53
23 : 1 77
20 : 1 65
18 : 1 76
16 : 1 73
17 : 1 82
19 : 1 71
18 : 1 75
Entry Solvent
Ligand Time (h) Yielda (%) drb
eec (%)
0
p-MeOC6H4
3,5-Me2C6H3
m-MeO2CC6H4
p-BrC6H4
p-ClC6H4
m-NO2C6H4
2-Thienyl
trans-PhCHQCH
cis-PhCHQCH
cis-p-MeOC6H4CHQCH 2l 72
cis-p-ClC6H4CHQCH 2m 96
cis-m-NO2C6H4CHQCH 2n 36
cis-p-MeO2CC6H4CHQCH 2o 36
cis-2-FurylCHQCH
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
MeCN
1,4-Dioxane 3g
PhMe
DCE
DCE
3f
3f
16
10
36
12
24
12
12
12
16
24
48
24
24
16
36
65
77
60
82
50
58
40
45
57
77
78
70
82
70
84
18 : 1
27 : 1 59
22 : 1 7
18 : 1 21
18 : 1 39
20 : 1 59
8 : 1 25
33 : 1 67
16 : 1
17 : 1 66
27 : 1 80
5 : 1 80
3a
3b
3c
3d
3e
3g
3h
3g
3g
9
10
11
12
13
14
15
16
0
2p 96
2q 64
3g
3g
3i
4 : 1 80
>99 : 1 80
>99 : 1 85
cis-2-ThienylCHQCH
a
b
Isolated yield of major diastereomer after purification. Determined
by 1H NMR analysis of the crude reaction mixture. Determined by
HPLC analysis.
c
a
b
Combined yield of two diastereomers after purification. Determined
by 1H NMR analysis of the crude reaction mixture. Determined by
c
HPLC analysis. Enantiomeric excess of major diastereomer reported.
d
K2CO3 (0.5 equiv.) used as base.
Using substrate 1a, the scope of the allene carbocyclisation
cascade with respect to the aryl or vinyl iodide was investigated
(Table 2). Gratifyingly, a range of electron-rich and electron-
poor aryl iodides bearing substituents in the meta- and
para-positions easily tolerated the reaction, with good yields
(76–86%) and enantioselectivities (86–89%) being obtained in
all cases (Table 2, entries 1–7). A variety of vinyl iodide sub-
strates were also found to be compatible with the cascade
reaction. It was observed that the cis-isomer of styryl iodide
(77% ee; Table 2, entry 10) provided much higher enantiomeric
excess compared to the corresponding trans-isomer (53% ee;
Table 2, entry 9). Therefore cis-vinyl iodides were used to
further explore the scope of this methodology, with the corre-
sponding products being obtained in good yields with good
Fig. 1 Chiral ligands screened during optimisation studies.
systems were found to be essential for achieving high levels of diastereo- and enantioselectivities (Table 2, entries 10–16).
enantiocontrol, with 1,2-dichloroethane giving a single diastereo- Pleasingly, no cis–trans isomerisation was observed when using
meric product in 70% yield and 80% ee (Table 1, entry 14). With vinyl iodides, demonstrating that both the products and
a significant level of enantioinduction already achieved the starting materials are configurationally stable under the reac-
final variable examined was the chiral ligand itself. A variety tion conditions.
of chiral ligands were purchased or prepared (Fig. 1) and then
Additionally, extension of this carbocyclisation cascade
examined in the optimisation study. With regard to the ligand methodology to structurally modified allene-linked indanone-
structure, it was observed that ligands forming six-membered derived pro-nucleophiles was readily achieved (Scheme 2). With
rings when coordinated to the Pd metal centre resulted in 3,5-dimethyl iodobenzene, a range of pro-nucleophiles with
products with higher enantioenrichment compared to the electron-donating or withdrawing substituents on the aromatic
ligands that form larger ring systems. The best enantioselec- ring of the indanone moiety, showed good compatibility
tivities were obtained using the bis(oxazoline) ligands, parti- with the cascade reaction. Yields were good to excellent
cularly ligand 3i which afforded a single diastereomer of 2a in with diastereoselectivities ranging from 21 : 1 to 53 : 1, whilst
85% ee and 84% yield (Table 1, entry 15). Interestingly, overly enantioselectivities ranged from 84–89% ee (4a–4f, Scheme 2).
bulky ligands such as 3h, imparted no enantiocontrol in the Variation of the nitrogen atom substituent to linear and
reaction. Overall, the optimal conditions were 1a (1.0 equiv.), branched alkyl chains did not significantly affect the reactivity
aryl iodide (1.5 equiv.), Ag3PO4 (0.5 equiv.), Pd(OAc)2 (10 mol%) or selectivity of the carbocyclisation (4g–4j, Scheme 2). The
and 3i (20 mol%) in DCE at 70 1C.
vinylative carbocyclisation with Z-configured styryl iodides also
c
5266 Chem. Commun., 2013, 49, 5265--5267
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and tolerating multiple points of diversity this reaction should
find use in complex natural product synthesis as well as
compound library production. Work to expand and apply these
findings is currently underway.
We gratefully acknowledge the University of Oxford and
Universities UK for an ORS Award (to M.L.), the EPSRC
(studentships to A.H. and D.M.B. and Leadership Fellowship
to D.J.D.), GlaxoSmithKline (studentship to A.H.), AstraZeneca
(studentship to D.M.B) and the FWO-Vlaanderen (P.B. and W.H.).
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Scheme 3 Carbocyclisation of pro-nucleophile 1l with 3,5-dimethyl iodobenzene.
successfully afforded the desired spirolactam products in high
yields (4k and 4l, Scheme 2).
Finally, N-tosylated g-lactam derived pro-nucleophile 1l,
a substrate less reactive than indanone-derived systems, under-
went cyclisation with 3,5-dimethyl iodobenzene to afford
spiropiperidin-2-one 4m in good yield with 83% ee (Scheme 3).
In the absence of a suitably crystalline spirocyclic product or
derivative for single crystal X-ray diffraction, the relative
configuration of spirolactams 2 and 4 were assigned by analogy
to our previous study5 and by NOESY analysis of compound 4b
(see ESI†). The absolute configuration was determined by
comparison of the measured and computed vibrational circular
dichroism (VCD) spectra.12 Using this method, the absolute
configuration of 4b was assigned as (2R,40S) with 99%
confidence.
In summary, we have developed a mild and efficient palladium 11 Y. Sato, M. Sodeoka and M. Shibasaki, Chem. Lett., 1990, 1953.
12 (a) E. De Gussem, P. Bultinck, F. Marion, J. Marchand-Brynaert,
catalysed enantio- and diastereoselective cyclisation cascade
methodology for the synthesis of a range of stereodefined arylated
C. V. Stevens and W. Herrebout, Phys. Chem. Chem. Phys., 2012,
14, 8562; (b) E. Debie, E. De Gussem, R. K. Dukor, W. Herrebout,
or vinylated spirolactam compounds. Being operationally simple
L. A. Nafie and P. Bultinck, ChemPhysChem, 2011, 12, 1542.
c
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Chem. Commun., 2013, 49, 5265--5267 5267