Copper-catalyzed iminoiodane-mediated aminolactonization of Olefins: Application to the synthesis of 5,5-disubstituted butyrolactones

Article abstract of DOI:10.1021/ol202436a

A copper(I)-catalyzed reaction of a variety of 4-aryl-pent-4-enoates with nosyliminoiodane generated in situ provides the corresponding 5-aryl-5-nosylamidomethylbutyrolactones. The reaction presumably proceeds via an aziridine intermediate, which could be

Full text of DOI:10.1021/ol202436a

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5830–5833
Copper-Catalyzed Iminoiodane-Mediated
Aminolactonization of Olefins: Application
to the Synthesis of 5,5-Disubstituted
Butyrolactones
Delphine Karila, Lo¨ıc Leman, and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette, France
robert.dodd@icsn.cnrs-gif.fr
Received September 8, 2011
ABSTRACT
A copper(I)-catalyzed reaction of a variety of 4-aryl-pent-4-enoates with nosyliminoiodane generated in situ provides the corresponding 5-aryl-5-
nosylamidomethylbutyrolactones. The reaction presumably proceeds via an aziridine intermediate, which could be isolated in one case.
The metal-catalyzed generation of nitrenes from the
hypervalent iodine arylsulfonyliminoiodane reagents Ar-
SO2NdIPh allows direct, mild, and generally high-yielding
formation of aziridines from olefins.1 Originally described
by Mansuy using metalloporphyrins as the catalysts,2 a
thorough investigation of this reaction was conducted by
Evans and co-workers who established that copper salts
were the most effective in generating the reactive metalla-
nitrene species from the iminoiodanes.3 Enantioselective
aziridinations, at least of the styrene-type olefins, could
furthermore be accomplished by including chiral ligands,
such as BOX ligands4 or diimines,5 in the reaction mixture.
The advent of one-pot procedures,6 in which the imi-
noiodane is generated directly in solution, considerably
improved the operational ease of this aziridination techni-
que since the tedious and sometimes delicate prior pre-
paration of the relatively unstable iminoiodanes was no
longer necessary (Scheme 1). The synthetic importance of
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D. J. Am. Chem. Soc. 1986, 108, 1079–1080. (c) Mahy, J.-P.; Bedi, G.;
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Bames, D. M. J. Am. Chem. Soc. 1993, 115, 5328–5329.
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r
10.1021/ol202436a
Published on Web 10/13/2011
2011 American Chemical Society

this aziridination procedure is reflected by its application
to an ever-growing list of natural product total syntheses.7
Scheme 3. Aminolactonization of Unsaturated Esters
Scheme 1. Asymmetric Copper-Catalyzed Iminoiodane-
Mediated Aziridination
Halolactonization of olefinic carboxylic acids or esters
is a well-known method for obtaining 5-halomethyl-γ-
lactones and particularly gem-disubstituted γ-lactones.8
Thus, treatment of a compound such as 2 (R0 = Me) with
a source of Iþ gives the 5-iodomethyl-5-methyl-γ-lactone 3
(Hal = I, Scheme 2). This type of reaction has been utilized
in a wide variety of synthetic strategies toward natural or
biologically active compounds.9 Whilesubstrate-controlled
stereoselectivehalolactonizationshavebeenwell-described,
recent research in this area has focused on the development
of reagent-controlled stereoselectivity. It occurred to us
that, by analogy with this halolactonization reaction, aziri-
dination of the same type of substrate, that is, an olefinic
ester or carboxylic acid 2, should follow a similar route
to give, after initial formation of the aziridine 4, amido-
methyl-γ-lactones of type 5 (Scheme 2). No reports of
such an aminolactonization reaction have, to the best of
our knowledge, been described.
ester. The corresponding lactone 9 was, however, obtained
with a lower yield of 30% as an inseparable 1:1 mixture
of diastereoisomers. While the above reactions provided
proof-of-concept regarding the viability of this novel amino-
lactonization reaction, the relatively low yields of product
can be attributed to the well-documented difficulty of this
aziridination reaction when applied to terminal olefins.1
With the objective of obtaining 5,5-disubstituted
γ-lactones, the above considerations encouraged us to
attempt the aminolactonization reaction starting from
styrene precursors known to be more reactive toward this
aziridination procedure. Thus, tert-butyl styrene-1-propa-
noate 10a was prepared in 94% yield by SuzukiꢀMiyaura
coupling of tert-butyl 4-bromo-4-pentenoate with phenyl-
boronic acid (see Supporting Information). Surprisingly,
when compound 10a was subjected to the same one-pot
aziridination procedure used for the formation of lactone
7, only starting material was recovered with no evidence of
formation of either the 10a-derived aziridine or aminolac-
tone 11a (Table 1, entry 1). However, when the reaction
was conducted in the presence of 12 mol % of chiral
BOX ligand A, a very satisfactory yield of 90% of the
5-phenyl-5-nosylamidomethyl-butyrolactone 11a was ob-
tained though with an ee of only 48% (entry 2).10 That an
amino ligand was necessary to allow the reaction to
proceed was demonstrated by replacement of the chiral
BOX ligand by achiral ethylenediamine (ligand C) which
also provided aminolactone 11a, though in somewhat
lower yield (72%, entry 3). Attempts were then made to
optimizethe yieldsof thisreaction. Changingthe solvent to
dichloromethane or benzene led in both cases to substan-
tial decreases in yield (51% and 25%, respectively) and ee’s
(4% and 20%) (entries 4 and 5) as did running the reaction
at 0 or ꢀ25 °C (entries 6 and 7). The same observation was
made when the Cu(MeCN)4PF6 catalyst was replaced by
Cu(PhCN)4ClO4 or (CF3SO3)2Cu (entries 8 and 9). Final-
ly, use of diimine B as a chiral ligand provided a high yield
of 11a (83%) but an almost negligible ee (5%, entry 10).
BOX ligand A was thus used in all the subsequent reactions
since yields were higher than with ligand B or C.
Scheme 2. Halolactonization vs Aminolactonization
In order to test our hypothesis, tert-butyl 4-methyl-4-
pentenoate 6 was subjected to the one-pot aziridination
procedure. Thus, to our delight, reaction of 6 with 1.2 equiv
each of nosylamide and iodosylbenzene in acetonitrile in
the presence of 25 mol % of tetrakisacetonitrile hexafluo-
rophosphate copper salt successfully provided 5-methyl-5-
nosylamidomethylbutyrolactone 7 in 56% yield with no
trace of the intermediate aziridine (Scheme 3).
This aminolactonization reaction was then successfully
extended to the β-methyl analogue 8 in the form of its ethyl
(9) (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 171–197.
(b) Rousseau, G.; Robin, S. Tetrahedron 1998, 54, 13681–13736.
(c) Hauske, J. R.; Julin, S. M. Tetrahedron Lett. 1993, 34, 4909–4912.
(d) Jung, M.; Ham, J.; Song, J. Org. Lett. 2002, 4, 2763–2765. (e) Kim, S.;
Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343–1345.
(10) Because the BOX ligands of type A as well as the salens of type B
are more adapted to stereoselective aziridination of 2- rather than
1-substituted styrenes, no further attempts were made to improve the
ee’s of the reactions described herein.
Org. Lett., Vol. 13, No. 21, 2011
5831

Table 1. Optimization of Aminolactonization Reaction Condi-
tionsa
Table 2. Scope of the Aminolactonization Reaction for the
Formation of gem-Disubstituted Lactonesa
entry
catalyst
solvent
temp ligand yield (ee)
(°C)
[%]
1
2
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
MeCN
MeCN
MeCN
CH2Cl2
C6H6
rt
rt
ꢀ
A
C
A
A
A
A
A
A
B
ꢀ
90 (48)
72 (00)
51 (04)
25 (20)
68 (35)
63 (33)
69 (24)
35 (10)
83 (05)
3
rt
4
rt
5
rt
6
MeCN
MeCN
0
7
ꢀ25
rt
8
Cu(PhCN)4ClO4 MeCN
9
(CF3SO3)2Cu
MeCN
MeCN
rt
10
Cu(MeCN)4PF6
rt
a All reactions were carried out with 1.2 equiv of NsNH2, 1.2 equiv of
˚
PhIO, 10 mol % [Cu], and 12 mol % ligand with 4 A molecular sieves.
To test the generality of this novel aminolactonization
reaction, the optimized conditions of Table 1 were applied
to a series of phenyl-substituted analogues 10 all prepared
in good to excellent yields by SuzukiꢀMiyaura coupling
(see Supporting Information). Compounds 10bꢀk were
then subjected to our standard aziridination/lactonization
conditions. As shown in Table 2, the o-, m-, and p-methoxy
derivatives 10bꢀd all gave excellent yields (83%, 91%,
86%) of the corresponding 5,5-disubstituted butyrolac-
tones 11bꢀd, respectively (entries 1ꢀ3). Similarly, the pre-
sence of three methoxy groups or an o-fluorine atom on the
aryl ring (10e, 10g) provided excellent yields of the corre-
sponding lactones 11e (93%) and 11g (79%), respectively
(entries 4 and 6).
In the case of derivative 10f, only compound 11f was
isolated in 72% yield as a result of competitive opening of
the intermediate aziridine by the adjacent o-methyl ester
(entry 5). The furan, thiophene, and indole derivatives
10hꢀj gave a slightly lower but acceptable yield of the
corresponding 5-heterocycle-substituted lactones 11hꢀj
(69%, 64%, and 62% yields, respectively, entries 7ꢀ9).
Finally, the ethylenedioxy derivative 10k afforded lactone
11k in 77% yield (entry 10).
a Reaction conditions: olefins (1.4 mmol), NsNH2 (1.8 mmol), PhIO
(1.8 mmol), Cu(MeCN)4PF6 (10 mol %), ligand A (12 mol %), MeCN,
˚
rt, 48 h under inert atmosphere with 4 A molecular sieves.
δ-lactone 13a (69%, Table 3, entry 1). Further elongation
of the chain as in compound 12b, however, provided only
the intermediate aziridine 13b, though in good yield (68%,
entry 2). Replacement of the ester groups of 11a and 12a by
an alcohol (12c and 12d, respectively) furnished the corre-
sponding tetrahydrofuran 13c and dioxane 13d in satisfy-
ing 66% and 67% yields (entries 3 and 4). Carbamates
rather than esters can also be successfully used in this pro-
cedure, the N-Boc derivative 12e providing the gem-dis-
ubstituted cyclic carbamate 13e in 50% yield (entry 5).
Finally, introduction of a stereogenic center on the sub-
strate as in the amino acid derivative 12f gave the highly
substituted γ-lactone 13f in 50% yield with a dr of 1.8:1
(entry 6).
The products obtained by this aminolactonization pro-
cedure can allow further elaboration to novel heterocyclic
systems. Thus, as shown in Scheme 4, treatment of lactone
11f withTFA inthe presence of sodium acetateindichloro-
methane gave the spiro lactone/lactam product 14 in
The optimized aziridination/lactonization reaction con-
ditions were also successfully extended to a variety of ole-
finic substrates 12aꢀf, all prepared by SuzukiꢀMiyaura
coupling of the appropriate starting materials (see Sup-
porting Information).
(11) (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151–161. (b)
Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.; Alvarez, M. Chem.;Eur.
ꢁ
J. 2011, 17, 1388–1408. (c) Tian, S. K.; Chen, Y.; Hang, J.; Tang, L.;
McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621–631. (d) Kacprzak,
Thus, extension of the chain length by one carbon
(i.e., substrate 12a) led to a surprisingly good yield of the
ꢁ
K.; Gawronski, J. Synthesis 2001, 961–998.
5832
Org. Lett., Vol. 13, No. 21, 2011

Table 3. Extension of the Aminolactonization Reaction for the
Formation of gem-Disubstituted Heterocycles
Scheme 4. Application of the Aminolactonization Reaction to
the Synthesis of Novel Heterocyclic Systems
C-3 functionalizedderivatives, veryfew of which have been
described.
In conclusion, we have developed a new, high yielding
aminolactonization procedure, analogous to the well-known
halolactonization reaction, resulting from iminoiodane-
mediated copper-catalyzed aziridination of styrene-
derived 1-propanoates (or butanoates). The aminolacto-
nization products can be further transformed into novel
highly functionalized heterocyclic systems such as 14 and
15. The full scope of this new reaction together with its
application to the synthesis of natural products is currently
in progress.
Acknowledgment. We wish to thank the Institut de
Chimie des Substances Naturelles for financial support
and fellowships. We also thank Dr. Meryem Benohoud
(ICSN) for preliminary experiments.
60% yield. Alternatively, reaction of the indole derivative
11j with NBS led to formation of the hexahydropyrrolo-
[2,3-b]indole spiro-lactone 15 in 76% yield (dr = 3.6:1).
The hexahydropyrrolo[2,3-b]indole motif is present in
a wide range of natural products and biologically active
compounds,11 and our method now allows easy access to
Supporting Information Available. Experimental de-
tails, characterization data and spectra (1H and 13C NMR)
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 21, 2011
5833