Enantioselective rhodium-catalyzed synthesis of α-chloromethylene- γ-butyrolactams from N-allylic alkynamides

Article abstract of DOI:10.1021/ol3017935

The first enantioselective cycloisomerization with intramolecular halogen migration of various 1,6-enynes promoted by a cationic Rh-Synphos catalyst is reported. This method provides an efficient route to enantiomerically enriched γ-butyrolactam derivatives, which are important core scaffolds found in numerous natural products and biologically active molecules. Good yields and enantiomeric excesses up to 96% are achieved.

Full text of DOI:10.1021/ol3017935

ORGANIC
LETTERS
2012
Vol. 14, No. 15
4006–4009
Enantioselective Rhodium-Catalyzed
Synthesis of r-Chloromethylene-
γ-Butyrolactams from N-Allylic
Alkynamides
Olivier Jackowski,† Jianping Wang,‡ Xiaomin Xie,‡ Tahar Ayad,† Zhaoguo Zhang,*,‡,§
and Virginie Ratovelomanana-Vidal*,†
Laboratoire Charles Friedel (LCF), Chimie ParisTech, CNRS UMR 7223, 75005
Paris, France, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai, 200240, China, and Shanghai Institute of
Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
Zhaoguo@sjtu.edu.cn; virginie-vidal@chimie-paristech.fr
Received July 3, 2012
ABSTRACT
The first enantioselective cycloisomerization with intramolecular halogen migration of various 1,6-enynes promoted by a cationic Rh-Synphos
catalyst is reported. This method provides an efficient route to enantiomerically enriched γ-butyrolactam derivatives, which are important core
scaffolds found in numerous natural products and biologically active molecules. Good yields and enantiomeric excesses up to 96% are achieved.
Ring systems abound in natural products and biologi-
cally active molecules, among which γ-butyrolactam struc-
tures are of preeminent importance since they are widely
spread in medicinal chemistry.1 Therefore, the develop-
ment of efficient methods for the stereoselective synthesis
of these relevant targets appears to be highly desirable. The
metal-catalyzed cycloisomerization2 reaction is an atom-
economical, challenging transformation for the rearrange-
ment of polyunsaturated compounds to cyclic derivatives.
Although cycloisomerization of 1,n-enynes has found
widespread use owing to the development of efficient cata-
lytic systems for the synthesis of carbo- and heterocycles,3
only a few examples of Pd-catalyzed cyclization reactions
(2) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b) Lloyd-Jones,
G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Fairlamb, I. J. S. Angew.
Chem., Int. Ed. 2004, 43, 1048. (d) Nieto-Oberhuber, C.; Lopez, S.;
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Jimenez-Nunez, E.; Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916.
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46, 4042. (g) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int.
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† Chimie ParisTech.
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‡ Shanghai Jiao Tong University.
Chem. Soc. Rev. 2009, 38, 3208. (k) Soriano, E.; Marco-Contelles, J. Acc.
Chem. Res. 2009, 42, 1026. (l) Pradal, A.; Toullec, P. Y.; Michelet, V.
Synthesis 2011, 1501. (m) Aubert, C.; Fensterbank, L.; Garcia, P.;
Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (n) Marinetti,
A.; Jullien, H.; Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884.
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Chem.;Eur. J. 1998, 4, 2405. (c) Trost, B. M.; Toste, D. J. Am. Chem.
Soc. 2000, 122, 714. (d) Sturla, S. J.; Kabalaeui, N. M.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 1976 and references therein. (e) Trost,
B. M.; Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651. (f) Trost,
B. M.; Czeskis, B. A. Tetrahedron Lett. 1994, 35, 211. (g) Goeke, A.;
Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1996,
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§ Shanghai Institute of Organic Chemistry.
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33, 580. (b) Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492. (c)
Qiao, L.; Wang, G.; George, C.; Lewin, N. E.; Blumberg, P. M.;
Kozikowski, A. P. J. Am. Chem. Soc. 1998, 120, 6629. (d) Feling,
R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen,
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10.1021/ol3017935
Published on Web 07/23/2012
2012 American Chemical Society

of 1,6-enynes to racemic R-halomethylene-γ-butyrolac-
tones and lactams have been reported, including our own
work.4 Zhang et al. first reported the cycloisomerization of
1,6-enynes promoted by a rhodium catalyst for the synthe-
sis of both racemic and enantioenriched γ-butyrolactones
with excellent yields and regio- and enantioselectivities.5 In
this context, we were interested in the rhodium-catalyzed
cyclization of 1,6-enynes with a halogen atom at the allylic
position through a π-allyl or enyl (σ þ π) rhodium
intermediate.6 The resulting exocyclic vinyl-chlorine struc-
ture would be suitable to undergo further cross-coupling
reactions and provides useful functionalized heterocyclic
compounds.
Initial investigations began with the cycloisomerization of
1a as a standard substrate using 20 mol % of catalyst,
prepared in situ from [Rh(COD)2]þXꢀ with various diphos-
phines at 50 °C in ClCH2CH2Cl for 24 h. In most of the
cases, the R-chloromethylene-γ-butyrolactam product 2a
was isolated in good to excellent yields and selectivities.
Examination of the results listed in Table 1 clearly
showed that the stereochemical outcome of the reaction
depended on the structure of the ligand considered. When
the reaction was carried out using (R)-Binap (L1),7 the
cyclized product 2a was obtained in 93% isolated yield and
with an encouraging enantiomeric excess of 81% (Table 1,
entry 1). To our delight, the (R)-Synphos ligand (L2)8
exhibited extremely high catalytic activity for the cyclo-
isomerization of 1a, providing 2a in 91% yield and with an
excellent ee of 96% (Table 1, entry 2). The use of the (S)-
Difluorphos (L3),9 (S)-Segphos (L4),10 and (S)-Sunphos
(L5)11 diphosphines, possessing a similar dihedral angle
but different electronic character, gave good enantioselec-
tivities ranging from 86 to 91%. These results indicate that
the electronic feature of the ligand has no significant
influence on the enantioselectivity (Table 1, entries 3ꢀ5).
In sharp contrast, the steric properties of the diphosphine
ligand, inparticular the arylsubstituentsatthe phosphorus
atom, play a crucial role in the stereochemical outcome of
the reaction, as outlined in Table 1.
Scheme 1. 1,6-Enyne Cyclization with Halogen Migration
This steric effect was revealed by comparison of the
selectivity of the reaction conducted with catalysts bearing
the Sunphos family of ligands (Table 1, entries 5ꢀ8). The
unsubstituted diphenyl Sunphos L5 and the corresponding
4-Me-C6H4 substituted diphosphine L6 afforded 2a, in
good to excellent yields with comparable selectivities
(Table 1, entries 5ꢀ6, 86 and 87% ee, respectively), while
much lower ee’s were observed with ligands L7 and L8,
which possess bulky aryl moieties on the phosphorus
(Table 1, entries 7 and 8, 59 and 33% ee, respectively).
Based onthe aboveresults, we found that(R)-Synphoswas
well suited for the cycloisomerization reaction. The nature
Since, in these cyclization reactions, a stereogenic center
is generated in the product 2 from a planar sp2-carbon in
the starting material 1, we envisaged the development of an
asymmetric version of these cycloisomerization reactions
using a combination of chiral diphosphine ligands and
rhodium complexes. We report herein the first enantiose-
lective Rh-catalyzedconstruction of R-chloromethylene-γ-
butyrolactams from N-tethered 1,6-enynes through
cycloisomerization with intramolecular halogen migration
(Scheme 1).
In our initial work on cyclization of alkynoates, we
demonstrated that the Rh(I)-rac-BINAP complex exhib-
ited high activity in this cycloisomerization reaction.6b
Therefore, we screened a number of chiral C2-symmetric
atropisomeric diphosphine ligands L1ꢀL8 that were com-
mercially available or developed in our laboratories (Table 1).
(7) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
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Genet, J.-P.; Dellis, P. WO Patent 03029259, 2003. (b) Duprat de Paule, S.;
Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P.
Eur. J. Org. Chem. 2003, 1931. (c) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Deschaux, G.;
Dellis, P. Org. Process Res. Dev. 2003, 7, 399. (d) Jeulin, S.; Ayad, T.;
Ratovelomanana-Vidal, V.; Genet, J.-P. Adv. Synth. Catal. 2007, 349,
1592. (e) Pautigny, C.; Jeulin, S.; Ayad, T; Zhang, Z.; Genet, J.-P.;
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2008, 350, 2525. (f)
Pautigny, C.; Debouit, C.; Vayron, P.; Ayad, T.; Ratovelomanana-
Vidal, V. Tetrahedron: Asymmetry 2010, 21, 1382. (g) Wu, Z.; Ayad, T.;
Ratovelomanana-Vidal, V. Org. Lett. 2011, 13, 3782.
(9) (a) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
Genet, J.-P.; Champion, N. Angew. Chem., Int. Ed. 2004, 43, 320. (b)
Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.;
Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5799.
(10) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(11) (a) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.; Pan, Y.;
Zhang, Z. Tetrahedron: Asymmetry 2004, 15, 2185. (b) Meng, Q.; Sun,
Y.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Zhang, Z. J. Org. Chem.
2008, 73, 3842. (c) Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Xie, X.;
Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z. J. Org. Chem. 2012, 77,
612. (d) Ma, X.; Li, W.; Li, X.; Tao, X.; Fan, W.; Xie, X.; Ayad, T.;
Ratovelomanana-Vidal, V.; Zhang, Z. Chem. Commun. 2012, 48, 5352.
(4) (a) Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 733.
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Org. Lett., Vol. 14, No. 15, 2012
4007

Table 1. Optimization of the Reaction Conditionsa
Table 2. Rh-Synphos-Catalyzed Cycloisomerization Reactiona
Rh catalyst
(mol %)
yield
(%)b
ee
(%)c
entry
ligand
X
1
L1
L2
L3
L4
L5
L6
L7
L8
L2
L2
L2
L2
L2
L2
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
PF6
20
20
20
20
20
20
20
20
20
20
15d
10d
5e
93
91
84
87
77
95
75
39
89
90
90
70
55
91
81 (R)
96 (R)
87 (S)
91 (S)
86 (S)
87 (R)
59 (R)
33 (S)
96 (R)
96 (R)
96 (R)
96 (R)
93 (R)
96 (R)
2
3
4
5
6
7
8
9
10
11
12
13
14
OTf
OTf
OTf
OTf
SbF6
15d
a All reactions were performed using 0.2 mmol of substrate 1a with
x mol % of Rh-catalyst, 1.1 x mol % of ligand in 2 mL of ClCH2CH2Cl.
b After flash chromatography. c Determined by chiral stationary phase-
supercritical fluid chromatography (CSP-SFC) or by HPLC analysis.
Absolute configuration was determined to be (R) by X-ray crystal-
lographic analysis. d Reaction run at 60 °C for 36 h. e Reaction run at
70 °C for 36 h.
a All reactions were performed using 0.2 mmol of substrate 1 with
15 mol % of Rh-catalyst, 16.5 mol % of ligand in 2 mL of ClCH2CH2Cl.
b After flash chromatography. c Determined by chiral stationary phase-
supercritical fluid chromatography (CSP-SFC) or by HPLC analysis.
Absolute configuration was determined to be (R) by X-ray crystallographic
analysis of 2a; the configurations of the other products were then assigned
by analogy. d Determined by 1H NMR analysis. e (S)-Segphos was used.
Figure 1. Structure determination for compound (þ)-2a by
X-ray crystallographic analysis.
of the noncoordinant counteranion did not seem to influ-
ence the catalytic activity or the enantioselectivity, as
4008
Org. Lett., Vol. 14, No. 15, 2012

similar results were obtained with different Rh pre-
ꢀ
but this result was still considerably lower than the one
obtained with compound 1a (Table 2, compare entry 1 vs 8).
A further demonstration of this substrate dependence was
illustrated by the cycloisomerization of enyne substrates
1iꢀm bearing an alkyl group on the acetylenic terminal
moiety. Pleasingly, good catalytic activity can be restored
when R is an ethyl, n-propyl, or n-butyl group, providing the
desired products 2iꢀk in good yields and selectivities
(Table 2, entries 9ꢀ11, 64 to 67% yield, 86 to 91% ee).
Furthermore, functionalized enynes 1lꢀm with benzyloxy
and chlorine atom substituents proved to be suitable sub-
strates for this transformation, affording compounds 2lꢀm
with higher enantioselectivities than those obtained with
2jꢀk (Table 2, entries 12 and 13, 51 to 68% yield, 88% ee).
In summary, we have developed an unprecedented en-
antioselective rhodium-catalyzed cycloisomerization of
N-tethered1,6-enyneswithanintramolecular halogen shift
leading to the corresponding R-chloromethylene-γ-butyro-
lactams in moderate to high isolated yields (up to 91%)
and withgood to excellent enantioselectivities (up to96%).
The functional group tolerance and substrate scope re-
ported here have not been demonstrated for any other
intramolecular halogen shift migration asymmetric cyclo-
isomerization reaction to date. On the other hand, our
useful cycloisomerization reaction can access functiona-
lized enantiomerically enriched R-chloromethylene-γ-
butyrolactams that are difficult to obtain otherwise. Further
studies on expanding the substrate scope and exploring the
synthetic utility of this reaction are currently underway in
our laboratories.
catalysts. Replacement of [Rh(cod)2]þSbF6 by either
[Rh(cod)2]þPF6 or [Rh(cod)2]þOTfꢀ provided 2a with
ꢀ
similar yields and enantioselectivities (Table 1, compare
entry 2 vs entries 9 and 10). Interestingly, the catalyst
loading could be reduced from 20% to 15% or 10%
without affecting the stereochemical integrity of the new
stereogenic center, although the reaction had to be con-
ducted at 60 °C for 36 h to reach completion (Table 1,
entries 11, 12, and 14). Finally, attempts to decrease the
catalyst loading further to 5 mol % gave rise to the desired
product 2a with lower yield and selectivity (Table 1, entry
13, 55% yield, 93% ee). The absolute configuration of the
R-chloromethylene-γ-butyrolactam product 2a was unam-
biguously established to be (R) based on a single-crystal
X-ray crystallographic analysis (Figure 1).12
Next, we evaluated the scope of this transformation.
Toward this end, several N-tethered 1,6-enyne derivatives
(1aꢀm) were prepared according to known procedures
and subsequently cycloisomerized under our optimized
ꢀ
reaction conditions using either [Rh(cod)2]þSbF6 or
[Rh(cod)2]þOTfꢀ as rhodium sources. As shown in
Table 2, both reactivity and enantioselectivity were influ-
enced by the nature of the N-protecting group. Indeed,
when comparing the results obtained with the N-tosyl
derivative 1a, reaction of enynes 1bꢀd bearing a benzyl,
phenyl, and methyl group provides the desired products
2bꢀd in significantly lower yields and enantioselectivities
(Table 2, compare entry 1 vs entries 2ꢀ4, 45 to 51% yield,
67 to 77% ee). The data of Table 2 also show that
this asymmetric CꢀC bond-forming reaction is highly
substrate-dependent.
Acknowledgment. We acknowledge the Centre National
ꢁ
A lower catalytic activity in terms of both reactivity and
selectivity was obtained with enyne substrates 1eꢀf bearing
an aromatic ring on the acetylenic terminal moiety (Table 2,
entries 5 and 6, 35 to 44% yield, 50% ee). A similarly
moderate enantioselectivity of 53% was obtained with the
nonsubstituted N-allylic alkynamide 1g (R = H), albeit
with a better isolated yield of 63% (Table 2, entry 7). A
significantly better enantiofacial discrimination was reached
for the cyclopropyl derivative 1h (Table 2, entry 8, 70% ee),
de la Recherche Scientifique (CNRS), the Ministere de
l’Education et de la Recherche, and the National Natural
Science Foundation of China for financial support of this
project.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for new com-
pounds (1H, 13C NMR, SFC/HPLC spectra) and the
crystallographic information file (CIF) for compound
(R)-2a. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) See Supporting Information. CCDC 885687 contains the supple-
mentary crystallographic data for this paper. These data for compound
(R)-2a can be obtained free of charge from The Cambridge Crystal-
lography Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
4009