Asymmetric iodolactonization utilizing chiral squaramides

Article abstract of DOI:10.1021/ol302798g

Asymmetric iodolactonization of γ- and δ-unsaturated carboxylic acids has been explored in the presence of six different chiral organocatalysts 5-8. The catalyst 6b was found to facilitate the cyclization of 5-arylhex-5-enoic acids 1 to the corresponding

Full text of DOI:10.1021/ol302798g

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5884–5887
Asymmetric Iodolactonization Utilizing
Chiral Squaramides
Jørn E. Tungen, Jens M. J. Nolsøe, and Trond V. Hansen*
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo,
P.O. Box 1068 Blindern, N-0316 Oslo, Norway
t.v.hansen@farmasi.uio.no
Received October 11, 2012
ABSTRACT
Asymmetric iodolactonization of γ- and δ-unsaturated carboxylic acids has been explored in the presence of six different chiral organocatalysts
5À8. The catalyst 6b was found to facilitate the cyclization of 5-arylhex-5-enoic acids 1 to the corresponding iodolactones 2 with up to 96% ee. By
this protocol, unsaturated carboxylic acids are converted enantioselectively to synthetically useful δ-lactones in high yields using commercially
available NIS. Apparently, both hydrogen bonding and aryl/aryl interactions are important for efficient stereodifferentiation.
Halolactonization, the intramolecular cyclization that
ensues as proximally unsaturated acids react through an
incipient halonium ion, is a powerful synthetic trans-
formation.1 Approximately 60 years ago, Woodward and
Singh demonstrated its relevance in total synthesis by
staging halolactonization as a linchpin feature in the
synthesis of the natural product allo-patulin.2 During the
intervening time, several eminent examples have appeared
in the literature,3 and halolactonization is now a well-
established tool in total synthesis.4,5 Over the past 30 years,
development of asymmetric versions of halolactonization,
in terms of substrate controlled reactions, has been met
with considerable success.6 However, asymmetric versions
under reagent control, in particular catalytic processes,
have proven more difficult to realize.7 Although good
asymmetric induction can be achieved when chlorine or
bromine is involved,8 the catalytic enantioselective iodo-
lactonization has only recently been communicated.9
(1) Selected reviews concerning halolactonization: (a) Snyder, S. A.;
Treitler, D. S.; Brucks, A. P. Aldrichimica Acta 2011, 44, 27. (b) Tan,
C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335. (c) Ranganathan, S.;
Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron 2004,
60, 5273. (d) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171.
(2) Woodward, R. B.; Singh, G. J. Am. Chem. Soc. 1950, 72, 5351.
(3) (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J. Am. Chem. Soc. 1969, 91, 5675. (b) Danishefsky, S.; Schuda, P. F.;
Kitahara, T.; Etheredge, S. J. J. Am. Chem. Soc. 1977, 99, 6066. (c) Zhou,
Q.; Snider, B. B. Org. Lett. 2008, 10, 1401.
(4) Selected reviews concerning iodolactonization in natural product
synthesis: (a) Laya, M. S.; Banerjee, A. K.; Cabrera, E. V. Curr. Org.
Chem. 2009, 13, 720. (b) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354.
(5) (a) Vik, A.; Hansen, T. V. Tetrahedron Lett. 2011, 52, 1060.
(b) Vik, A.; Hansen, T. V.; Holmeide, A. K.; Skattebøl, L. Tetrahedron
Lett. 2010, 51, 2852. (c) Langseter, A. M.; Skattebøl, L.; Stenstrøm, Y.
Tetrahedron Lett. 2012, 53, 940. (d) Holmeide, A. K.; Skattebøl, L.;
Sydnes, M. J. Chem. Soc., Perkin Trans. 1 2001, 1942. (e) Stivala, C. E.;
Gu, Z.; Smith, L. L.; Zakarian, A. Org. Lett. 2012, 14, 804. (f) Canham,
S. M.; France, D. J.; Overman, L. E. J. Org. Chem. 2012 10.1021/
jo300872y. (g) Snyder, S. A.; Wright, N. E.; Pflueger, J. J.; Breazzano, S. P.
Angew. Chem., Int. Ed. 2011, 50, 8629.
(6) (a) Takano, S.; Murakata, C.; Imamura, Y. Heterocycles 1981, 16,
1291. (b) Hart, D. J.; Huang, H.-C.; Krishnamurthy, R.; Schwartz, T.
J. Am. Chem. Soc. 1989, 111, 7507. (c) Fuji, K.; Node, M.; Naniwa, Y.;
Kawabata, T. Tetrahedron Lett. 1990, 31, 3175. (d) Yokomatsu, T.;
Iwasawa, H.; Shibuya, S. J. Chem. Soc., Chem. Commun. 1992, 728. (e)
Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett.
1999, 40, 8827.
(7) (a) Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T.
J. Chem. Soc., Chem. Commun. 1992, 1005. (b) Grossman, R. B.; Trupp,
R. J. Can. J. Chem. 1998, 76, 1233. (c) Haas, J.; Piguel, S.; Wirth, T. Org.
Lett. 2002, 4, 297. (d) Haas, J.; Bissmire, S.; Wirth, T. Chem.;Eur. J.
2005, 11, 5777. (e) Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org.
Chem. 2007, 3281.
(8) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298. (b) Yousefi, R.; Whitehead, D. C.;
Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608.
(c) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W.
J. Am. Chem. Soc. 2010, 132, 3664. (d) Zhou, L.; Tan, C. K.; Jiang, X.;
Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474. (e) Murai,
K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.;
Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174.
r
10.1021/ol302798g
Published on Web 11/13/2012
2012 American Chemical Society

Preceding the rendition given here, the highest level of
stereocontrol had been obtained based on a tentative
H-bonding motif being present in the organocatalyst,
which used a urea scaffold.9c The increased attention on
squaramides as a novel H-bonding catalophore for asym-
metric synthesis10À13 prompted us to investigate their ability
to promote enantioselective iodolactonization (Scheme 1).
Table 1. Catalyst Screening of Squaramides 5À8 in the Reaction
between δ-Unsaturated Acid 1a and NIS/I2
Scheme 1. Development of Asymmetric Iodolactonization
Utilizing Chiral Squaramide Organocatalysts
yield
(%)b
ee
(%)c
entrya
catalyst
1
2
3
4
5
6
5a
5b
6a
6b
7
83
84
74
81
15
85
8
10
43
42
11
0
8
a The reactions were performed on a 0.2 mmol scale. b Isolated material.
c Determined by HPLC analysis using commercial chiral columns.
In our study of iodolactonization, δ-unsaturated acid 1a
(R = H) was selected as a model substrate for protocol
development (Table 1). A collection of squaramides 5À8
was prepared (see Supporting Information) and subjected
to screening (Figure 1). Having prenominated dichloro-
methane as the reference solvent, the reactions were run
at À78 °C for 24 h with a fixed starting concentration of
25 mM. Equimolar amounts of substrate and N-iodosuc-
cinimide (NIS) were used, while the catalyst loading and
the I2 additive were both held at 15 mol %.
Based on the initial findings, it was evident that squar-
amide 6a and 6b were practically equipotent and provided
the best asymmetric induction (entries 3 and 4). Converse-
ly, among the squaramides 5À6, the presence of a benzyl
motif proved vastly inferior to the aryl motif (entries 1 and 2).
Further insight into the catalytic activity of the catalo-
phore was gained by subsequently omitting or modifying
certain structural features. In the absence of a benzyl or a
phenyl motif, squaramide 7 displayed some weak intrinsic
asymmetric induction conferred by the chiral diamino
(9) (a) Wang, M.; Gao, L. X.; Wen, P. M.; Xia, A. X.; Wang, F.;
Zhang, S. B. J. Org. Chem. 2004, 69, 2874. (b) Ning, Z. L.; Jin, R. H.;
Ding, J. Y.; Gao, L. X. Synlett 2009, 2291. (c) Veitch, G. E.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2010, 49, 7332. (d) Ning, Z.-L.; Ding, J.-Y.;
Jin, R.-Z.; Kang, C.-Q.; Cheng, Y.-Q.; Gao, L.-X. Chem. Res. Chin.
Univ. 2011, 27, 45. (e) During our investigations and preparation of this
manuscript a highly enantioselective protocol for iodolactonization was
disclosed, utilizing Brønsted acid catalysis: Dobish, M. C.; Johnston,
J. N. J. Am. Chem. Soc. 2012, 134, 6068.
Figure 1. Squaramide catalysts investigated in this study.
(10) Reviews on H-bonding catalysis in asymmetric synthesis: (a)
Pihko, P. M. Hydrogen bonding in Organic Synthesis; Wiley-VCH: 2009.
(b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (c) Pihko,
P. M. Angew. Chem., Int. Ed. 2004, 43, 2062. (d) Schreiner, P. R. Chem.
Soc. Rev. 2003, 32, 289.
functionality (entry 5). On the other hand, when the chiral
diamino moiety itself was altered, interchanging the ter-
tiary amine for a carbamate, racemic 2a was obtained
(entry 6).
Having identified seemingly suitable catalysts, the en-
antioselectivity was subsequently examined in terms of
solvent effects (Table 2). In the first run (entries 1À12),
squaramide 6a was assessed. Among the solvents tested it
was found that, whereas acetone was conducive for obtain-
ing higher ee-values (entry 9), dichloromethane provided
a better chemical yield (entry 1). By combining the two
solvents it was possible to retain the achieved ee-value
(11) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416.
(12) Review of squaramides as organocatalysts: Aleman, J.; Parra,
ꢀ
A.; Jiang, H.; Jørgensen, K. A. Chem.;Eur. J. 2011, 17, 6890.
€
(13) (a) Noole, A.; Jarving, I.; Werner, F.; Lopp, M.; Malkov, A.;
Kanger, T. Org. Lett. 2012, 14, 4922. (b) Sun, W.; Zhu, G.; Wu, C.;
Hong, L.; Wang, R. Chem.;Eur. J. 2012, 18, 6737. (c) Albrecht, Ł.;
Dickmeiss, G.; Acosta, F. C.; Rodrıguez-Escrich, C.; Davis, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543. (d) Ling, J.-B.;
Su, Y.; Zhu, H.-L.; Wang, G.-Y.; Xu, P.-F. Org. Lett. 2012, 14, 1090.
(e) Yang, H.-J.; Dai, L.; Yang, S.-Q.; Chen, F.-E. Synlett 2012, 23, 948.
(f) Dai, L.; Yang, H.; Niu, J.; Chen, F.-E. Synlett 2012, 23, 314.
Org. Lett., Vol. 14, No. 23, 2012
5885

while increasing the chemical yield (entry 12). However, it
became clear that squaramide 6a could not be easily
swayed to deliver iodolactone 2a beyond 54% ee. Thus,
in a second run, squaramide 6b was assessed (entries
13À16). Gratifyingly, when the reaction was performed
in acetone (entry 14), the difference between the catalysts
was demonstrable, as iodolactone 2a could be obtained in
80% ee, albeit in moderate chemical yield. Employing the pre-
cognized solvent combination of acetone/dichloromethane
effectively enhanced the chemical yield (entry 15).
Table 3. Screening of Conditions in the Squaramide Catalyzed
Asymmetric Reaction of δ-Unsaturated Acid 1a with NIS/I2
yield
(%)b
ee
entrya catalyst
conditions
30 mol % cat.
(%)c
Table 2. Solvent Screening in the Squaramide Catalysed
Asymmetric Reaction of δ-Unsaturated Acid 1a with NIS/I2
1
6a
30
53
60
6
57
47
87
71
70
87
87
87
87
85
82d
2
6a
2.0 equiv NIS
3
6b
30 mol % cat.
4
6b
1 mol % I2
5
6b
30 mol % I2
81
74
72
70
83
64
79
6
6b
c = 0.1 M
7
6b
c = 0.2 M
8
6b
30 mol % cat., c = 0.1 M
c = 0.1 M, 50% v/v CH2Cl2
as entry 9 but w. 100 mol % cat.
c = 0.1 M, 50% v/v CH2Cl2
9
6b
10
11
6b
yield
(%)b
ee
ent-6b
entrya
catalyst
solvent
CH2Cl2
(%)c
a The reactions were performed on a 0.2 mmol scale. b Isolated
material. c Determined by HPLC analysis using commercial chiral
columns. d Antipodal 2a was formed with opposite stereochemistry.
1
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
74
72
75
0
43
21
37
n.d.
n.d.
41
9
d
2
CHCl3
3
toluene
4
hexane
DMFd
5
0
was generally followed by a decrease in ee (entries 2, 4,
and 5).
6
THF
11
8
7
Et2O
At the outset, it was found that squaramides 5À6 only
dissolved poorly in a range of organic solvents. This raised
the question as to whether the reaction at low temperature
proceeded in a heterogeneous or homogeneous fashion.
However, when δ-unsaturated acid 1a was added to a
suspension of squaramide 6b in acetone/dichloromethane,
instantaneous dissolution occurred. Thus, the aggregate
of substrate and catalyst is highly soluble. Presumably,
δ-unsaturated acid 1a and squaramide 6b form an ion pair
through an acid/base reaction. This is substantiated by the
fact that squaramide 6b also dissolves easily in acetic acid
and acidified acetone. To corroborate whether the catalyst
was indeed performing at its optimum under the given
conditions, a 1:1 mixture of δ-unsaturated acid 1a and
squaramide 6b was subjected to reaction. The good corre-
spondence between the catalytic and stoichiometric experi-
ments (entries 9 and 10) instilled confidence in the
procedure.
After having established satisfactory conditions for the
asymmetric conversion of δ-unsaturated acid 1a to the
corresponding iodolactone, the scope of the protocol was
tested against a series of different substrates (Table 4).
As the results were accrued a causal connectivity became
evident, demonstrating that the enantioselectivity was
subject to electronic modulation.
When δ-unsaturated acid 1 contained an electron-
deficient aryl moiety, the asymmetric induction was ele-
vated compared to the reference substrate and iodolac-
tones 2eÀ2g were obtained in 90 to 96% ee. Juxtaposed, an
electron-rich aryl moiety caused the level of asymmetry to
8
EtOAc
65
56
9
45
53
7
9
acetone
10
11
12
13
14
15
16
EtOH
i-PrOH
0
n.d.
54
42
80
81
80
acetone/CH2Cl2 1:1
CH2Cl2
86
81
60
84
74
acetone
acetone/CH2Cl2 1:1
acetone/toluene 1:1
a The reactions were performed on a 0.2 mmol scale. b Isolated material.
c Determined by HPLC analysis using commercial chiral columns. d The
reaction was performed at À61 °C.
Finally, a screening was performed in order to examine
the effects of concentration, additives, and catalyst loading
(Table 3). The best result was achieved when the concentra-
tion was quadrupled, using 1:1 acetone/dichloromethane
(entry 9), yielding iodolactone 2a in 87% ee and 83%
chemical yield.
The constellation of N-iodoimides and I2 in the presence
ofprotic acid has beenshown torender a triiodide cation,14
which promotes the iodolactonization at low tempera-
ture.9c For our purpose, commercial NIS and I2 was
sufficient to achieve the desired transformation within
24 h. Nonetheless, the reaction proved to be sensitive
in one respect; the ratio between NIS, I2, and catalyst was
of importance. Deviation from the established conditions
(14) Chaikovskii, V. K.; Funk, A. A.; Filiminov, V. D.; Petrenko,
T. V.; Kets, T. S. Russ. J. Org. Chem. 2008, 44, 935.
5886
Org. Lett., Vol. 14, No. 23, 2012

Table 4. Asymmetric Reaction of δ-Unsaturated Acid 1 with
NIS/I2 Catalyzed by Squaramide 6b
Table 5. Asymmetric Reaction of γ-Unsaturated Acid 3 with
NIS/I2 Catalyzed by Squaramide 6b
yield of 4
(%)b
ee of 4
(%)c
yield of 2
(%)b
ee of 2
(%)c
entrya
R-groups in 3 and 4
entrya
R-groups in 1 and 2
1
2
3a, 4a: phenyl
86
85
7d
14
1
2
3
4
5
6
7
8
1a, 2a: phenyl
83
91
80
87
83
78
73
77
87
92
86
12
90
96
91
16
3b, 4b: p-chlorophenyl
1b, 2b: 2-naphthyl
1c, 2c: p-tolyl
a The reactions were performed on a 0.2 mmol scale. b Isolated
material. c Determined by HPLC analysis using commercial chiral
columns. d Apparent inversion of configuration by HPLC analysis.
1d, 2d: p-anisyl
1e, 2e: p-fluorophenyl
1f, 2f: p-chlorophenyl
1g, 2g: p-bromophenyl
1h, 2h: i-propyl
acceptable enantioselectivity. The lack of a rigid fit between
the substrate and catalyst in the stereodifferentiating step
is borne out by an apparent configurational inversion of
iodolactone 4a relative to iodolactone 4b. Yet, the as-
signment of iodolactones 4a and 4b is substantiated by a
previous report of the compounds.9c
a The reactions were performed on a 0.2 mmol scale. b Isolated
material. c Determined by HPLC analysis using commercial chiral
columns.
be severely demoted and 2d was obtained in only 12% ee.
Interestingly, while the presence of a p-tolyl moiety in
δ-unsaturated acid 1 was comparable to a phenyl, 86%
ee for 2c and 87% ee for 2a respectively, the presence of a
2-naphthyl caused the level of asymmetry to rise to 92% ee
for 2b. Whether the latter can be attributed to steric
encumbrance or aryl/aryl interaction between the sub-
strate and catalyst is an open question. It was observed,
however, that the replacement of an aryl group with an
isopropyl group was detrimental to the enantioselectivity,
with only 16% ee for 2h. This could be taken to indicate
the necessity of aryl/aryl interactions for efficient stereo-
differentiation.
Next, we turned our attention toward applying squar-
amide 6b to γ-unsaturated acid 3 (Table 5). For kinetic
reasons,15,16 the transition from δ-iodolactone 2 to
γ-iodolactone 4 was anticipated as a more challenging
asymmetric transformation, in view of the poor induction
obtained with reactive substrate 1d (vide supra).
As the experiments were conducted, this premonition
was echoed in the results. Thus, when γ-unsaturated acid 3
only contained a phenyl group, the stereochemical out-
come was diminutive, with 7% ee for 4a. The result was
somewhat ameliorated when γ-unsaturated acid 3 carried
an electron-deficient aryl moiety, yielding 14% ee for 4b.
However, based on these findings, the constellation of
substrate and catalyst clearly needs to be evaluated
anew in order to deliver γ-iodolactones 4a and 4b with
Bromolactonization of δ-unsaturated acids 1 catalyzed
by squaramide 6b is currently under investigation. The
preliminary findings have revealed a more sluggish reac-
tion with moderate asymmetric induction: Cyclization
of acid 1a in the presence of N-bromosuccinimide (NBS)
afforded the corresponding δ-bromolactone in 58% ee and
30% chemical yield after 24 h. Thus, the protocol featured
in this communication does not translate directly to effi-
cient asymmetric bromolactonization.
In conclusion, we have developed a highly enantioselec-
tive protocol for iodolactonization of δ-unsaturated acids
by the use of the novel squaramide 6b as an efficient
organocatalyst. Our approach compares favorably with
those already published in terms of enantioselectivity,9a,b,d
substrate concentration, reaction time, and simplicity of
execution.9c
Acknowledgment. J.E.T. is thankful for a Ph.D. schol-
arship from The School of Pharmacy, University of Oslo.
The Norwegian Research Council (KOSK II) is gratefully
acknowledged for a scholarship to J.M.J.N. The authors
are indebted to Mr. Thor H. K. Thvedt at The Norwegian
University of Science and Technology for performing
GLC analyses of δ-iodolactone 2h.
Supporting Information Available. Experimental pro-
1
13
cedures and characterization data, HÀ C NMR, MS,
and HRMS spectra as well as chromatograms of HPLC
and GLC analyses. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(16) (a) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(b) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476. (c) Baldwin, J. E.;
Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
5887