Squaramide catalyzed enantioselective iodolactonization of allenoic acids

Article abstract of DOI:10.1016/j.tetlet.2016.10.035

An asymmetric iodolactonization reaction of allenoic acids has been extensively studied. Eight different chiral squaramides were prepared in a straightforward manner and investigated as organocatalysts. The reaction protocol is operationally simple to exe

Full text of DOI:10.1016/j.tetlet.2016.10.035

Accepted Manuscript
Squaramide catalyzed enantioselective iodolactonization of allenoic acids
Renate Kristianslund, Marius Aursnes, Jørn Eivind Tungen, Trond Vidar
Hansen
PII:
S0040-4039(16)31338-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.035
TETL 48205
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 August 2016
5 October 2016
10 October 2016
Please cite this article as: Kristianslund, R., Aursnes, M., Tungen, J.E., Hansen, T.V., Squaramide catalyzed
enantioselective iodolactonization of allenoic acids, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.10.035
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Graphical Abstract
Squaramide catalyzed enantioselective
iodolactonization of allenoic acids
Leave this area blank for abstract info.
Renate Kristianslund, Marius Aursnes, Jørn Eivind Tungen, Trond Vidar Hansen

1
Tetrahedron Letters
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Squaramide catalyzed enantioselective iodolactonization of allenoic acids
Renate Kristianslund, Marius Aursnes, Jørn Eivind Tungen, Trond Vidar Hansen∗
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo,
Norway
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An asymmetric iodolactonization reaction of allenoic acids has been extensively studied. Eight
different chiral squaramides were prepared in a straightforward manner and investigated as
organocatalysts. The reaction protocol is operationally simple to execute and proceeds with up to
76% enantiomeric excess. Several conditions, additives, catalysts and substrates have been
investigated. The best results were observed with 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-
(((1R,2R)-2-(dipentylamino)cyclohexyl)amino)-cyclobut-3-ene-1,2-dione as the catalyst.
Available online
Keywords:
2015 Elsevier Ltd. All rights reserved.
Squaramides
Iodolactonization
Allenoic acids
Stereoselective synthesis
H-bonding
Halocyclization reactions are useful synthetic transformations
that have been applied to the synthesis of various natural
products and bioactive compounds.1 Recently, asymmetric
versions have been developed for a wide variety of synthetic
bromolactonization protocol was accomplished in the presence of
a chiral dinuclear gold complex and/or chiral phosphate anions.8
N-Bromolactams proved superior as the halogenating agent with
up to 99% enantiomeric excess in several examples. However,
when N-iodosuccinimide (NIS) was used for the synthesis of
vinylic iodolactones, no asymmetry was induced.8 In 2014, the
group of Hennecke disclosed the first organocatalytic
enantioselective bromolactonization protocol in the presence of a
dimeric cinchona alkaloid derived catalyst.9 These authors
observed that the selectivity was variable; the highest ee-value
was 72%. Of note, Hennecke and co-workers reported low
selectivity in the presence of some trisimidazoline derived
catalysts for the bromolactonization products.9 Later in 2014,
Murai, Shimizu and Fujioka reported the first enantioselective
iodolactonization protocol using allenoic acids.10 These authors
reported that in the presence of iodine and an analogue of the
trisimidazoline catalyst attempted by the Hennecke group,
selectivity with up to 82% ee was observed for some cases.10
Experiments supported that a π-allyl complex intermediate was
most likely involved.10
transformations,
including
halolactonizations,2
cyclohaloaminations,3 cyclohaloetherifications,4 and other
reactions involving halofunctionalizations.5 Alkenes are most
commonly employed, however, enynes have also been utilized
for the formation of synthetically useful products.6 Only very
recently have allenes been investigated as substrates (Scheme 1).
Previously we disclosed highly enantioselective iodo-11 and
bromo-lactonization12 protocols utilizing chiral squaramides,
such as 1-8 (Fig. 1). The halolactone products were obtained in
high to excellent yields with up to 96% ee for both reaction
types.11,12 Chiral squaramide derived catalysts have recently been
employed in many asymmetric reactions.13 This fact, combined
with our interest in employing halolactones in natural product
synthesis,12,14 spurred our interest to investigate the asymmetric
iodolactonization reactions of allenoic acids in the presence of
catalysts 1-8 (Fig. 1). These efforts are communicated herein.
Scheme 1. Outline of the iodocyclization of δ-1,1-disbustituted
allenoic acids.
When we initiated our studies towards the development of an
enantioselective iodolactonization protocol using allenoic acids,
only a few studies had been reported.7,8 Ma and co-workers
reported the highly diastereoselective, substrate-controlled
iodolactonization of such acids.7 These studies revealed that the
planar chirality of an allene is transferred to the iodolactone
products.7 Toste and co-workers disclosed
———
a
highly
enantioselective bromocyclization of allenes.8 This formal
∗ Corresponding author. Tel.: +47-22-855-470; fax: +47-228 5-947; e-mail: t.v.hansen@farmasi.uio.no

Tetrahedron
2
(Entry 8). Reducing the temperature to -78 °C gave a slight
increase in ee (12%) using CH2Cl2 as the solvent (Entry 9), while
a 1:1 CH2Cl2:acetone mixture gave an even better selectivity. In
this case, 10a was formed with 42% ee in a modest 31% yield
(Entry 10). EtOAc, acetone, THF, Et2O or isopropanol all gave
low enantiomeric excess of 10a at -78 °C, with considerably
varied yields (Entries 11-15). Of note, in toluene at -78 °C, (R)-
configured 10a was formed with 44% ee (Entry 16). The 1:1
solvent mixture of CHCl3:hexane returned 10a with 25% ee
(Entry 17). Gratifyingly, a 1:1 mixture of CHCl3:acetone
improved the selectivity to 52% ee; in this case 10a was obtained
in low yield (Entry 18). Similar selectivity was seen using a 1:1
mixture of 1,2-dichloroethane:acetone (47% ee) (Entry 19).
Table 2. Screening of solvents in the asymmetric
iodolactonization reaction.
Figure 1. Squaramide catalysts investigated in this study.
Ee
Entrya
1
Solvent
Temp. (°C)
Yield (%)b
(%)c
9
We started our screening efforts by employing the
squaramide catalysts 1-4, NIS and I2 in CH2Cl2 at 0 °C for the
enantioselective iodolactonization reaction with 9a as the model
substrate. Based on our previous experience11 and literature
reports,2c the amounts of NIS and I2 were 1.0 equivalent and 15
mol%, respectively. Pleasingly, under these conditions, the
iodocyclization of allenoic acid 9a afforded only the 5-exo
cyclization product 10a. However, the enantioselectivity was
disappointingly low (ee = 9%) (Table 1, entry 1). The absolute
configuration was established as (S) by comparison of the
specific optical rotation values of 10a with literature values.10
CH2Cl2
0
49
33
32
34
33
26
39
52
8
2
Acetone
0
3
3
3
Toluene
0
4
CHCl3
0
7
5
EtOAc
THF
0
9
6
0
3
7
Et2O
0
4
8
CH2Cl2/acetone (1:1)
CH2Cl2
0
6
Table 1. Screening of squaramide catalysts 1-4 in the asymmetric
iodolactonization reaction
9
- 78
- 78
- 78
- 78
- 78
- 78
- 78
- 78
- 78
- 78
- 78
12
42
10
18
16
4
10
11
12
13
14
15
16
17
18
19
CH2Cl2/acetone (1:1)
EtOAc
31
35
8
Acetone
THF
18
7
Et2O
Isopropanol
12
15
8
9
Entrya
1
Catalyst
Yield (%)b
49
Ee (%)c
Toluene
44d
25
52
47
9
1
CHCl3/hexane (1:1)
CHCl3/acetone (1:1)
1,2-Dichloroethane/acetone (1:1)
2
3
4
22
54
38
9
5
4
2
3
4
19
13
c
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H chiral column. dThe (R)-enantiomer was
formed as determined by HPLC analysis and specific optical rotation values.
c
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H chiral column.
We then investigated the importance of the iodine source
(Table 3) with squaramide 1 as the catalyst, as this often
influences the selectivity.2c,11 The presence of both NIS and I2
proved to be important, and the amount of iodine influenced both
the yields and the ee-values (Entries 1-3). In the absence of I2, the
product was obtained in lower yield while the enantioselectivity
remained unaltered (Entry 6), in comparison to using NIS
together with 15 mol% I2 (Entry 5). Using only iodine gave
racemic 10a (Entry 7), while increasing the amount of iodine
compared to NIS diminished the selectivity (Entries 3, 8). The
use of diiodohydantoine (DIH, Entry 4) gave a low yield with
similar selectivity as NIS.
Product 10a was also produced with similar low ee-values in
the presence of catalysts 2-4 (Table 1, entries 2-4). In terms of
both enantioselectivity and yield, catalyst 1 provided the best
results. Previously, we have observed that altering the solvent
and reaction conditions utilizing catalyst
1
in the
iodolactonization of alkenoic acids11 significantly enhanced the
selectivity. Hence, we wanted to investigate if the selectivity in
the iodocyclization of allene substrate 9a was also amenable to
such alterations (Table 2). The use of acetone, toluene, CHCl3,
EtOAc, THF or Et2O at 0 °C resulted in very low asymmetric
induction with varied yields (Entries 2-7). The best yield (52%)
was observed using a 1:1 mixture of CH2Cl2:acetone as solvent

3
Table 3. Screening of I+-source in the asymmetric
subjected to the improved conditions as described above (Table
iodolactonization reaction.
6). The electronic properties of the substituents gave rise to
differences in the selectivity. Electron-donating substituents in
the para-position returned almost racemic products 10b and 10c
(Entries 2, 3), while 3,5-dimethyl substitution provided 10d in
37% ee (Entry 4). Substrates 9e and 9f with either a fluoro- or a
chloro-substituent in the para-position, respectively, were next
examined. Substrate 9e gave similar results for product 10e as for
product 10a (Entry 5), while an improvement with respect to
enantioselectivity was observed using 9f. In this case, the vinylic
δ-iodolactone 10f was obtained with 75% ee and 22% isolated
yield. The para-CF3-substituted substrate 9g gave product 10g
with 69% ee (Entry 6). The nitro-group in the para-position gave
the highest selectivity (76% ee), but a very poor yield was
observed for product 10h (< 5%). Similar poor yields were
obtained for product 10i which was formed with an enantiomeric
excess of 53%.
Yield
(%)b
ee
(%)c
Entrya
I+ source
Solvent
1
2
3
4
5
6
7
8
I2 (5 mol%), NIS (1.0 equiv.)
I2 (15 mol%), NIS (1.0 equiv.)
I2 (65 mol%), NIS (1.0 equiv.)d
DIH (0.5 equiv.)
CHCl3/acetone (1:1)
CHCl3/acetone (1:1)
CHCl3/acetone (1:1)
CHCl3/acetone (1:1)
CH2Cl2/acetone (1:1)
CH2Cl2/acetone (1:1)
CH2Cl2/acetone (1:1)
CH2Cl2/acetone (1:1)
c
12
19
31
14
31
15
14
28
48
52
37
41
42
43
0
I2 (15 mol%), NIS (1.0 equiv.)
NIS (1.5 equiv.)
Table 5. Screening of catalysts 5-8.
I2 (1.5 equiv.)
I2 (1.0 equiv.), NIS (1.0 equiv.)e
9
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H chiral column. dPortionwise addition of I2
over 96 hours. e72 h reaction time.
Since additives and altering the concentrations of the starting
materials have also been reported to alter the enantioselectivity in
the presence of chiral squaramides,11,12 we performed some
additional experiments (Table 4). Reducing the concentration of
the substrate diminished the selectivity (Entry 1), while doubling
the concentration returned similar results (Entry 2). The use of
molecular sieves did not enhance the yield or the selectivity
(Entry 3). Increasing the amount of catalyst (Entry 4), or the
reaction time (Entry 5), as well as using additives (Entries 6-8),
returned similar selectivities in the range of 35-50% ee. In all
cases, the yields of 10a were low.
Entrya
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
24
21
15
19
0
3
5
6
7
8
0
45
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H chiral column.
c
Table 6. Substrate scope of the asymmetric iodolactonization
reaction.
Table 4. Screening of conditions in the asymmetric
iodolactonization reaction.
1 (
cat. 15 mol%),
NIS (1.0 equiv.),
I2 (15 mol%)
I
O
O
CO2
H
CHCl3/acetone (1:1),
conditions,
- 78 °C, 24 h
10a
9a
Entrya
Ar (9, 10)
Yield (%)b
ee (%)c
52
5
Yield
(%)b
ee
(%)c
Entrya
Conditions
c = 0.025 Md
c = 0.20 M
1
2
3
4
5
6
7
8
9
9a, 10a: C6H5
19
81
5
9b, 10b: 4-MeO-C6H4
9c, 10c: 4-tert-Bu-C6H4
9d, 10d: 3,5-Me2-C6H3
9e, 10e: 4-F-C6H4
1
2
3
4
5
6
7
8
11
22
15
28
18
14
28
11
28
2
48
41
50
45
48
46
35
11
14
22
13
< 5
< 5
37
50
75
69
76
53
3Å MS, 96 hd, e
100 mol% catalyste
96 he
9f, 10f: 4-Cl-C6H4
9g, 10g: 4-CF3-C6H4
9h, 10h: 4-NO2-C6H4
9i, 10i: 4-CN-C6H4
2,6-di-tert-butylpyridine (2.5 equiv.)e
4-(N,N-dimethylamino)pyridine (0.1 equiv.), 96 he
4-(N,N-dimethylamino)pyridine (1.0 equiv.), 72 he
c
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H and Chiralpak AD-H chiral columns.
c
aReactions performed on a 0.1 mmol scale of 9a. bIsolated yield. Determined by HPLC
analysis using the commercial Chiralcel OD-H chiral column. dReaction was performed
using CH2Cl2/acetone (1:1). eConcentration of 9a was 0.1 M.
Next we tried the conditions in Table 6 with 4-phenylhexa-
4,5-dienoic acid (11) as the substrate (Scheme 2). This produced
the corresponding vinylic γ-iodolactone 12 in near quantitative
yield, but with very poor enantiomeric excess (6%). These types
of substrates are more difficult to engage in highly stereoselective
reactions due to the rapid cyclization to the γ-iodolactones.11,12,15
The improved conditions were then applied with catalysts 5-8
(Table 5). All four catalysts were less selective than 1 (Entries 1-
4), with only catalyst 8 able to induce any reasonable asymmetry
in the product 10a (Entry 4). In this case, 10a was obtained in
45% ee and 19% isolated yield. To explore the substrate scope
with respect to selectivity, several substrates were prepared and

Tetrahedron
4
135, 1232-1235; (d) Alix, A.; Lalli, C.; Retailleau P.;
Masson, G. R. J. Am. Chem. Soc. 2012, 134, 10389-
10392; (e) Zhou, L.; Tay, D. W.; Chen, J.; Leung, G. Y.
C.; Yeung, Y.-Y. Chem. Commun. 2013, 49, 4412-4414.
4. Examples of asymmetric cycloetherifications: (a) Tan,
C. K.; Yu, W. Z.; Yeung, Y. Chirality 2014, 26, 328-343;
(b) Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun, W.
Chem. Commun. 2013, 49, 2418-2420; (c) Hennecke,
U.; Müller, C. H.; Fröhlich, R. Org. Lett. 2011, 13, 860-
863; (d) Denmark, S. E.; Burk, M. T. Org. Lett. 2012,
14, 256-259; (e) Huang, D.; Wang, H.; Xue, F.; Guan,
H.; Li, L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350-
6353.
Scheme 2. Organocatalyzed iodolactonization reaction with 4-
phenylhexa-4,5-dienoic acid (11).
To summarize, we have investigated the enantioselective
organocatalyzed iodolactonization reaction of aryl-substituted δ-
unsaturated allenoic acids 9a-i using eight different squaramides.
Only low to modest enantiomeric excess of products 10a-i were
observed, with up to 76% ee in the best case. Unfortunately,
these synthetically useful products were obtained in low yields
due to the low conversions at -78 °C of all substrates
investigated, except the para-methoxy substituted substrate 9b.16
Efforts towards improving both the enantioselectivity and the
chemical yields are ongoing. Since chiral squaramides are easily
available over a few steps, their application in enantioselective
protocols will most likely continue to rise.13 Along with prior
demonstrations of highly enantioselective halocyclization
reactions,11,12 we hope that the initial results reported herein will
stimulate further developments of organocatalyzed reactions for
the preparation of synthetically useful vinylic iodolactones.
Chiral squaramides have many advantages, such as their
insensitivity to moisture and oxygen, low toxicity and ease of
preparation from low cost starting materials.13 Only recently have
squaramide derived organocatalysts been employed for the
synthesis of non-12 and halogenated natural products.17
Considering their large number,17 enantioselective and catalytic
processes using these types of catalysts will most likely be used
for their preparation.
5. (a) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei
I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664-
3665; (b) Wilking, M.; Mueck-Lichtenfeld, C.;
Daniliuc, C. G.; Hennecke, U. J. Am. Chem. Soc. 2013,
135, 8133-8136; (c) Rauniyar, V.; Lackner, A. D.;
Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681-
1684.
6. (a) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.;
Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132,
3664-3665; (b) Zhang, W.; Hu, X.; Xu, H.; Tang, W. J.
Am. Chem. Soc. 2009, 131, 3832-3833.
7. (a) Jiang, X.; Fu, C.; Ma, S. Chem. Eur. J. 2008, 14,
9656-9664; (b) Lü, B. ; Jiang, X.; Fu, C.; Ma, S. J. Org.
Chem. 2009, 74, 438-441; (c) Zhang, X.; Fu, C.; Yu, Y.;
Ma, S. Chem. Eur. J. 2012, 18, 13501-13509.
8. Miles, D. H.; Marcos, V.; Toste, F. D. Chem. Sci. 2013,
4, 3427-3431.
9. Wilking, M.; Daniliuc, C. G.; Hennecke, U. Synlett
2014, 25, 1701-1704.
10. Murai, K.; Shimizu, N.; Fujioka, H. Chem. Commun.
2014, 50, 12530-12533.
11. Tungen, J. E.; Nolsøe, J. M. J.; Hansen, T. V. Org. Lett.
2012, 14, 5884-5887.
Acknowledgments
12. Aursnes, M.; Tungen, J. E.; Hansen, T. V. J. Org. Chem.
2016, 81,8287–8295 .
13. (a) Han, X.; Zhou, H.-B.; Dong, C. Chem. Rec. 2016,
16, 897-906; (b) Storer, R. I.; Aciro, C.; Jones, L. H.
Chem. Soc. Rev. 2011, 40, 2330-2346;
Helpful discussions with Associate Professor Anders Vik are
appreciated. The Norwegian Research Council (FRIPRO-
FRINATEK 230470) is gratefully acknowledged for scholarships to
R. K. and M. A., while we thank the School of Pharmacy, University
of Oslo, for a scholarship to J. E. T.
14. (a) Primdahl, K. G.; Stenstrøm, Y.; Hansen, T. V.; Vik,
A. Chem. Phys. Lipids 2016, 196, 1-4; (b) Filippova, L.;
Aarum, I.; Ringdal, M.; Dahl, M. K.; Hansen, T. V.;
Stenstrøm, Y. Org. Biomol. Chem. 2015, 13, 4680-4685;
(c) Jacobsen, M. G.; Vik, A.; Hansen, T. V. Tetrahedron
Lett. 2014, 55, 2842-2844; (d) Jacobsen, M. G.; Vik, A.;
Hansen T. V. Tetrahedron Lett. 2012, 53, 5837-5839; (e)
Vik, A.; Hansen, T. V. Tetrahedron Lett. 2011, 52, 1060-
1062; (f) Vik, A.; Hansen, T. V.; Holmeide, A. K.;
Skattebøl, L. Tetrahedron Lett. 2010, 51, 2852-2854;
(g) Hansen, T. V.; Skattebøl. L. Tetrahedron Lett. 2004,
45, 2809-2811.
References and notes
1. (a) Laya, M. S.; Banerjee, A. K.; Cabrera, E. V. Curr.
Org. Chem. 2009, 13, 720-730; (b) Snyder, S. A.;
Treitler, D. S.; Brucks, A. P. Aldrichimica Acta 2011,
44, 27-40.
2. (a) Hennecke, U. Chem. – Asian J. 2012, 7, 456-465;
(b) Nolsøe, J. M.; Hansen, T. V. Eur. J. Org. Chem.
2014, 3051-3065; (c) Veitch, G. E.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2010, 49, 7332-7335; (d) Chen,
G.; Ma, S. Angew. Chem., Int. Ed. 2010, 49, 8306-8308;
(e) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011,
1335-1339; (f) Filippova, L.; Stenstrøm, Y.; Hansen, T.
V. Tetrahedron Lett. 2014, 55, 419-422; (g) Arai, T.;
Kojima, T.; Watanbe, O.; Itoh, T.; Kanoh, H.
ChemCatChem. 2015, 7, 3234-3428; (h) Denmark, S.
E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed.
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N. J. Am. Chem. Soc. 2012, 134, 6068-6071.
15. Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111,
6513-6556.
1
16. Conversion was determined to be < 60% by H NMR-
analyses; full conversion was observed for 9b.
17. (a) Chung, W.; Vanderwal, C. D. Angew. Chem., Int. Ed.
2016, 55, 4396-4434; (b) Martin, T.; Padron, J. I.;
Martin, V. S. Synlett 2013, 12-32.
1
Copies of H and 13C NMR spectra and of chromatograms of
3. Examples of asymmetric haloaminocyclizations: (a)
Bovino, M. T.; Chemler, S. R. Angew. Chem., Int. Ed.
2012, 51, 3923-3927; (b) Chen, J.; Zhou, L.; Yeung, Y.-
Y. Org. Biomol. Chem. 2012, 10, 3808-3811; (c) Chen,
F.; Tan C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013,
HPLC analyses, as well as experimental procedures, are available
at [to be inserted by editorial office].

Highlights:
A highly regioselective synthesis of vinylic iodolactones is reported.
A robust, practical and operationally simple protocol for the preparation of chiral squaramide catalysts is
demonstrated.
The reported organocatalyzed protocol renders the use of metals or special pre-cautions unnecessary.
The chiral catalysts investigated returned enantiomeric excess of up to 76%.
Useful vinylic iodolactones were obtained as products.