An asymmetric iodolactonization reaction catalyzed by a zinc bis-proline-phenol complex

Article abstract of DOI:10.1016/j.tetlet.2013.11.028

The intramolecular zinc bis-proline-phenol complex 2a was found to promote enantioselective iodolactonization reactions of both electron-rich and electron-poor 5-aryl-5-hexenoic acids affording δ-iodolactones in good chemical yields with up to 82% enantio

Full text of DOI:10.1016/j.tetlet.2013.11.028

Tetrahedron Letters 55 (2014) 419–422
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Tetrahedron Letters
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An asymmetric iodolactonization reaction catalyzed by a zinc
bis-proline–phenol complex
a,b
Liudmila Filippova a, Yngve Stenstrøm a, , Trond Vidar Hansen
⇑
a Department of Chemistry, Biology and Food Science, Norwegian University of Life Sciences, PO Box 5003, N-1432 Ås, Norway
b School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, Blindern, PO Box 1068, N-0316 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Revised 6 November 2013
Accepted 12 November 2013
Available online 16 November 2013
The intramolecular zinc bis-proline-phenol complex 2a was found to promote enantioselective iodolact-
onization reactions of both electron-rich and electron-poor 5-aryl-5-hexenoic acids affording d-iodolac-
tones in good chemical yields with up to 82% enantiomeric excess. The reactions were found to be
insensitive to air and moisture, providing an experimentally simple protocol for synthetically useful
compounds.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Iodolactonization
d-Iodolactones
Trost ligand
Zinc complex
The halolactonization of alkenoic acids has been known for
more than a century.1 This reaction presents an attractive route
to halolactones which can be key intermediates in the synthesis
of natural products and are used as starting materials for further
synthetic transformations.2 Catalytic enantioselective versions of
halolactonizations have been developed, but mostly for chloro-
and bromo-lactonization reactions.3 Some reagent-controlled and
selective iodolactonization protocols have been reported.4–6 For
example, Taguchi and co-workers reported the use of one equiva-
tion reaction of several 4-aryl-4-pentenoic acids to give c-lactones
with up to 85% ee.7b Veitch and Jacobsen7c reported that 5-aryl-
5-hexenoic acids underwent iodolactonizations in the presence of
a tertiary aminourea catalyst yielding the desired d-iodolactones
in high chemical yields with ee values between 48% and 96%. Dob-
ish and Johnston7d employed a chiral Brønsted acid catalyst in their
studies of the same type of acids; the obtained aryl substituted d-
iodolactones had ee values between 57% and 96%. In addition Han-
sen and co-workers7e recently published their work on using
squaramides as organocatalysts for obtaining d-iodolactones with
enantiomeric excesses between 12% and 96% with 5-aryl-5-hexe-
noic acids as substrates. The research group of Martin7f reported
a BINOL-derived, bifunctional catalyst that was employed for the
preparation of a few d-iodolactones in high yields and with ee val-
lent of a chiral titanium complex in the synthesis of
c-lactones
with 65% ee.4 Grossman and Trupp5 reported, in 1998, the first suc-
cessful reagent-controlled enantioselective iodolactonization.
However, the stereoselectivity was disappointingly low with ee
values in the range of 3–7%, and as such demonstrated the princi-
ple without any practical impact. Rousseau and co-workers6 re-
ues P98%; several c-iodolactones were obtained in a highly enan-
ported the preparation of 5-endo-
c-lactones with ee values
tioselective manner with the same catalyst.
between 10% and 20% in the presence of stoichiometric amounts
of a chiral silver-ephedrine complex. Although some improve-
ments were made in the enantioselectivity, it was still very low.
The first catalytic, enantioselective iodolactonization was reported
in 2004 by Gao and co-workers.7a using quaternary ammonium
salts derived from cinchonidine, but with only moderate enanti-
In connection with our ongoing projects on the synthesis of
polyunsaturated fatty acid derived natural products employing
iodolactonizations,8 we became interested in developing a new
enantioselective protocol. The commercially available semi-
azacrown ether ligand 19 and the corresponding di-nuclear zinc
complexes 2a and 2b (Fig. 1) attracted our attention.10 The dinucle-
ar zinc complex 2a has successfully been applied in a large variety
of asymmetric transformations.11 Similarly the bis-proline derived
ligand 1, containing two tertiary amines and a phenol, could exhi-
bit catalytic activity in an enantioselective iodolactonization. The
tertiary amines should provide H-bonding motifs12 which have
been reported to be of great importance in some organocatalytic
oselectivity. Moreover, the formation of mixtures of both
c- and
d-lactones was observed. The same group later reported that a
salen-Co(II) complex catalyzed the enantioselective iodolactoniza-
⇑
Corresponding author. Tel.: +47 64965893; fax: +47 64965901.
E-mail address: yngve.stenstrom@umb.no (Y. Stenstrøm).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.028

420
L. Filippova et al. / Tetrahedron Letters 55 (2014) 419–422
R
Zn
O
However, the observed enantiomeric excess of 55–74% in the
Ph
Ph
Ph
Ph
HO
OH N
Ph
Ph
O
Ph
Ph
OH
N
O
O
reaction catalyzed by 2a varied in the individual experiments.
The addition of 0.15 equiv of iodine did not enhance the selectivity
(entry 4). Employing the adduct 2b, with the more bulky iso-propyl
group, afforded iodolactone 4a with improved yield, but with low-
er ee values. Again, low reproducibility was observed (entry 5). Our
first concern was the lack of a strict control of moisture content.
Surprisingly, the addition of 4 Å molecular sieves to the reaction
mixture caused a drop in enantioselectivity (entries 6 and 7). The
reaction conditions were then investigated. A solvent screen re-
vealed that toluene was the best solvent (entries 2, 8–11). Further
changes in the reaction conditions in terms of catalyst loadings,
variations in concentration, amount of iodine added, the use of so-
dium bicarbonate as base, or altering the reaction times, did not
enhance the enantioselectivity. To our surprise, the complex 2a
showed catalytic activity even after slow evaporation of the sol-
vent and storage of the residue without any precautions against
moisture and air. However, significant improvement in the repro-
ducibility of the results was observed (Table 1, entry 12). This reac-
tion was performed three times with the same results with respect
to the yield and enantiomeric excess. These data suggest that
in situ generated complex 2a might act as a precatalyst with the
formation of an even more active catalyst by contact with air
and/or moisture. This was also supported by the above-mentioned
observation that the addition of 4 Å molecular sieves gave a drop in
the enantioselectivity. Unfortunately, our attempts to isolate crys-
tals suitable for X-ray analysis were not successful. The nature of
the active catalytic species therefore remains unknown. However,
it has been reported that 2a might form oxo-bridged dimers, such
as 5 (Fig. 1), in the presence of adventitious amounts of water.11
The addition of ethanol to the in situ generated complexes 2a
has been reported to alter the formation of the alkoxy-bridged
dinuclear zinc species 6 as a result of exchange of the labile alkyl
group.11 We then performed the enantioselective iodolactonization
reaction with the addition of ethanol to complex 2a. These exper-
iments yielded similar and results reproducible with those ob-
tained in the absence of ethanol using the obtained solid (entry
13).
Zn
N
N
2a: R = Et
1
2
2b: R = i-Pr
O
OR
Ph
Ph
O
Ph
Ph
Ph
Ph
O
Ph
Ph
O
Zn
O
Zn
O
Zn
N
Zn
N
N
N
2
6
5
Figure 1. Structures of the semi-azacrown ether ligand 1, the dinuclear zinc
complex 2, the oxo-bridged dimer 5, and the alkoxy derivative 6.
iodolactonizations.7c,e Herein, we report the results of our study on
asymmetric iodolactonization mediated by the zinc complex 2a.
Initially, the ability of the Trost-ligand 1 to catalyze the iodol-
actonization of 5-phenylhex-5-enoic acid (3a) in the presence of
N-iodosuccinimide (NIS) in toluene at À20 °C was investigated.
The ligand 1 yielded the racemic product 4a in 30–48% yield
(Table 1, entries 1 and 2). The 1H NMR spectrum of a 1:10 mixture
of 1 and 3a, respectively, revealed that the chemical shift values of
the alpha protons in 3a were only slightly affected (see Fig. 2b). On
the other hand, 1H NMR-analyses of various mixtures of 2a and
3a showed a linear effect on the
Dd-values for the protons at C2
in 3a indicating weak interactions between the acid and the
zinc-complex (Fig. 2c and Supplementary data).
Moreover, the 13C NMR spectra of mixtures of 2a and 3a also re-
vealed the same type of interactions (see Supplementary data).
These NMR observations encouraged us to use the adduct 2a, pre-
viously reported by Trost et al.,9,10a as a catalyst in an enantioselec-
tive iodolactonization protocol. Adding a THF solution of 2a to a
solution of 3a and NIS in toluene yielded the desired iodolactone
4a in 70% chemical yield with variable enantioselectivity (Table 1,
entry 3).
Table 1
Investigation of the reaction conditions
I
O
NIS
catalyst (10 mol%)
temperature
additive
Ph
OH
Ph
O
O
3a
4a
Entrya
Catalyst
Solvent
Additive
°C
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13f
14
15
1
1
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
—
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À40
0
72
24
70
24
24
70
70
70
70
70
70
48
48
48
24
30
48
70
68
80
62
71
72
66
84
65
70
71
70
74
Racemic
Racemic
55–74
50
57–62
44
27
31
57
31
0.15 equiv I2
—
0.15 equiv I2
—
4 Å MS
4 Å MS
—
—
—
—
—
EtOH
—
2ad
2ad
2bd
2ad
2ad
2ad
2ad
2ad
2ad
2ae
2ae
2ae
2ae
THF
Et2O
CH2Cl2
Me2CO
PhMe
PhMe
PhMe
PhMe
30
76
74
82
—
72
a
b
c
d
e
f
The reactions were carried out with acid 3a (0.2 mmol), catalyst (0.02 mmol), and NIS (0.22 mmol) in solvent (4 mL) in the absence of light.
Isolated yield as an average of at least two experiments.
Determined by using HPLC with a chiral stationary phase (see supporting data for details).
In situ generated solution. The reactions were run under protection from air and moisture.
Solid residue after evaporation of THF from the catalyst solution.
The catalyst was obtained by addition of a stoichiometric amount of ethanol to an in situ generated solution of 2a.

L. Filippova et al. / Tetrahedron Letters 55 (2014) 419–422
421
Figure 2. 1H NMR spectroscopic study (400 MHz in CDCl3): (a) 3a; (b) 1:10 mixture of 1 and 3a; (c) 1:10 mixture of 2a and 3a.
The next step in our efforts to improve the enantioselective iod-
olactonization reaction using complex 2a was to lower the temper-
ature to À40 °C. This led to a slight increase in the selectivity with
the iodolactone 4a formed with 82% ee and in 70% yield (Table 1,
entry 14). However, at À78 °C the reaction was sluggish and did
not go to completion. Raising the temperature to 0 °C increased
notably the reaction rate, but lowered the ee value to 72% (entry
15). In summary, the best result was achieved at À40 °C in toluene
yielding iodolactone 4a in 70% yield and 82% ee.
Having established the conditions for the enantioselective
iodolactonization of 3a, we next applied them to a panel of
5-aryl-substituted 5-hexenoic acids. As shown in Table 2, good
yields with ee values between 59% and 82% were observed for
these substrates with either electron-rich or electron-deficient aryl
substituents (Table 2). The electron-deficient substrates were less
reactive and prolonged reaction times were necessary to achieve
good conversions. The level of asymmetric induction was strongly
diminished for the reaction of reactive electron-rich substrate 3f;
the lactone 4f was obtained with 32% ee. The absolute configura-
tion of the products 4a–4f was determined to be S by comparison
with authentic samples7f and literature optical rotations.7c–f When
replacing the phenyl group with an n-butyl group, the correspond-
ing product 4g was returned with a poor ee value of 12%. Also, the
opposite absolute configuration was observed for this product.7e
When the antipode of the ligand 1 was applied, the R-configured
product 4 was formed with the same enantiomeric excess (com-
pare Table 2, entries 1 and 8).
Table 2
Iodolactonization of substituted 5-hexenoic acids mediated by 2aa
NIS (1.1 equiv)
I
O
2a (10 mol%)
R
OH
R
O
O
toluene
-40 °C
3
4
Entry
Substrate
Product
Yieldb (%)
eec (%)
1
2
3a: R = Ph
3b: R = 2-Np
4a
4b
4c
4d
4e
4f
70
69
87
82
70
71
68
70
82
60
62
70
59
32
12
83
3
3c: R = p-MeC6H4
3d: R = p-ClC6H4
3e: R = p-BrC6H4
3f: R = p-MeOC6H4
3g: R = n-Bu
4d
5
6
7
4g
4h
8e
3a: R = Ph
a
b
c
Reactions were run on 0.1 mmol scale employing complex 2a in solid form.
Isolated yield after purification by column chromatography.
Determined by HPLC using chiral columns.
The reaction was run for 72 h.
Catalyzed by the zinc complex generated from the antipode of ligand 1.
d
e
the iodolactones in good yields and with enantioselectivities up to
82% under mild conditions. The protocol reported herein was not
shown to be air and/or moisture sensitive. Further studies will con-
centrate on gaining a better understanding of the nature of the ac-
tive catalytic species, as well as the origin of the enantioselectivity
for further improvements and to expand the substrate scope.
´
In summary, we have demonstrated the application of Trosts
Acknowledgment
dinuclear zinc complex 2a in a catalytic, enantioselective iodolact-
onization reaction with 5-aryl-5-hexenoic acids in the presence of
commercially available NIS. No additives were necessary to afford
Financial support to L.F. from the Norwegian University of Life
Sciences (The Quota Scheme) is gratefully acknowledged.

422
L. Filippova et al. / Tetrahedron Letters 55 (2014) 419–422
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Supplementary data
6. Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281.
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Chem. 2004, 69, 2874; (b) Ning, Z. L.; Jin, R. H.; Ding, J. Y.; Gao, L. X. Synlett 2009,
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Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068; (e) Tungen, J. E.;
Nolsøe, J. M. J.; Hansen, T. V. Org. Lett. 2012, 14, 5884; (f) Fang, C.; Paull, D. H.;
Hethcox, J. C.; Shugrue, C. R.; Martin, S. F. Org. Lett. 2012, 14, 6290.
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(b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572; (c) Trost, M. B.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.
028.
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