Tertiary aminourea-catalyzed enantioselective iodolactonization

Article abstract of DOI:10.1002/anie.201003681

Binding the anion : A highly enantioselective iodolactonization of 5-hexenoic acids has been achieved using a tertiary aminourea-catalyst (see scheme). The use of catalytic iodine in this process is critical to enhancing both the reactivity and enantioselectivity of the stoichiometric I⁺ source. The mechanism is proposed to involve binding of an iodonium imidate intermediate by the H-bond donor catalyst.

Full text of DOI:10.1002/anie.201003681

Communications
DOI: 10.1002/anie.201003681
Asymmetric Catalysis
Tertiary Aminourea-Catalyzed Enantioselective Iodolactonization**
Gemma E. Veitch and Eric N. Jacobsen*
The intramolecular reaction of carboxylic acids with pendant
Table 1: Optimization studies for the enantioselective iodolactonization
of 2a.
olefins in the presence of a source of I+—the iodolactoniza-
tion reaction—is a powerful method for the generation of
five- and six-membered lactones [Eq. (1)]. Diastereoselective
variants of this reaction provide efficient access to stereo-
chemically defined lactones, and consequently this reaction
has found widespread use in natural products synthesis.[1] In
contrast, the development of catalytic enantioselective var-
iants has proved challenging,[2,3] a problem likely associated
with the inherent difficulty of controlling the reactivity of
iodonium ion intermediates through intermolecular interac-
tions.[4]
Entry[a]
I+ Source
I2 Additive
[mol%]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
4
5
6
I2
4
5
5
0
0
0
0
3
–
50
30
66
92
94
88
25
12
95
98
85
–
15
15
30
The recent discovery of anion-binding mechanisms in H-
bonding catalysis[5] has opened the door to the development
of asymmetric catalytic methods that engage reactive cationic
intermediates such as N-acyliminum ions,[6] N-protioiminium
ions,[7] acylpyridinium ions,[8] aziridinium ions,[9] and oxocar-
benium ions.[10] We were intrigued by the possibility that
analogous pathways might be available to iodonium ions,
thereby providing the control over halonium ion reactivity
that is necessary for enantioselective iodolactonization and
related reactions. Herein, we report the successful application
of such a strategy in the development of a tertiary aminourea-
catalyzed asymmetric iodolactonization reaction.
The iodolactonization of hexenoic acid derivative 2a was
selected as a model reaction for catalyst and reagent screen-
ing studies. A broad survey of potential H-bond donor
catalysts revealed that bifunctional tertiary aminourea deriv-
atives were required to induce useful levels of catalysis. A
sharp dependence on the amino group substituents was
observed, with di-n-pentyl derivative 1 affording highest
enantioselectivities.[11] Whereas N-iodoimides or I2 alone
proved poorly reactive (Table 1, entries 1–4), the combination
[a] Reactions performed on a 0.05 mmol scale. [b] Determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as the internal stan-
dard. [c] Determined by HPLC analysis using commercial chiral columns.
of stoichiometric levels of an N-iodoimide derivative and
catalytic I2 was found to produce a high-yielding and highly
enantioselective system for iodolactonization (entries 5 and
6). It has been shown recently that N-iodoimides undergo
conversion to the corresponding triiodide cations upon treat-
ment with I2 and a protic acid,[12] and this provides a likely
explanation for the synergistic effect of these reagents in the
present system. However, increasing the I2 loading above that
of the chiral catalyst (1) led to measurable decreases in
enantioselectivity (entry 7). Variation of the identity of the N-
iodoimide resulted in small but measurable changes in the
enantioselectivity of the reaction, with N-iodo-4-fluoroph-
thalimide derivative 5 proving optimal.[13] The sensitivity of
the product ee to the structure of the imidate suggests a direct
involvement of this counterion in the enantiodetermining
step.
[*] Dr. G. E. Veitch, Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology, Harvard University
12 Oxford St, Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
Low-temperature 1H NMR studies were performed in an
effort to gain insight into the mechanism of the iodolactoni-
zation reaction. In the presence of N-iodo-4-fluorophthal-
imide (5) and catalytic iodine, catalyst 1 was found to undergo
a rapid reaction to yield a compound with spectroscopic and
reactivity properties consistent with the N-iodo complex 7
(Scheme 1).[14] Intermediate 7 can be quenched with aqueous
sodium thiosulfate to regenerate the starting tertiary amine
catalyst 1 as well as the corresponding secondary amine. The
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-43214) and by
postdoctoral fellowships to G.E.V. from the Fulbright Commision
and the Royal Society for the Exhibition of 1851. We acknowledge
Mitchell Denti for experimental assistance and Dr. Eugene Kwan for
helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003681.
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Chemie
reactive substrates (3g–3i), it was
necessary to use 2 equivalents of the
iodinating agent 5 to achieve useful
conversions.
To determine the absolute config-
uration of 3a, a radical deiodination
was performed to provide the corre-
sponding, known methyl lactone.[16]
This assignment was confirmed by X-
ray crystallographic analysis of the 4-
bromo derivative 3g.[17]
These reaction conditions proved
ineffective with the corresponding
pentenoic
acid
substrate
10a
(Table 2, R = H), providing the iodo-
lactonization product 11a in low enan-
tiomeric excess (entry 1). However,
enantioselectivities were improved
substantially by decreasing the loading
of iodine additive, with best results
obtained using 0.1 mol% of I2
(entry 3). The rate of racemic iodolac-
tonization in the absence of 1 is not
affected by the concentration of added
I2, so it appears that the inverse
relationship between ee and I2 loading
may be due to competing pathways
promoted by 1. In that context, it is
Scheme 1. Proposed catalytic cycle for the iodolactonization of 2.
Table 2: Optimization studies for the enantioselective iodolactonization
of pentenoic acid derivative 10a.
latter is presumably formed from 7 by elimination of HI and
subsequent iminium hydrolysis.
A proposal for the mechanism of iodolactonization
catalysis is outlined in Scheme 1. Iodonium ion formation
from hexenoic acid 2 is presumably induced by N-iodo
tertiary aminourea 7. Subsequent cyclization is proposed to
take place as the rate- and enantiodeterminng step, based on
the observation of differing reactivities, under otherwise
identical conditions, of pentenoic, hexenoic, and heptenoic
acid substrates to generate the corresponding 5-, 6-, and 7-
Entry[a]
Substrate
I2 Additive
[mol%]
Yield [%][b]
ee [%][c]
1
2
3
10a
10a
10a
10a
10b
15
1.0
0.1
0.1
0.1
86
95
45
82
98
31
76
90
90
0
membered lactone products (5 > 6
@ 7). Preliminary
computational studies support the intermediacy of iodonium
ion complex 8, which maintains a tertiary amino–iodonium
ion interaction.[15] On the basis of this putative structure, we
suggest that urea-bound phthalimide serves as the base to
effect deprotonation of the carboxylic acid in the enantiode-
termining cyclization event. An alternative mechanism in
which deprotonation is induced by the tertiary amino group
present in the catalyst is also plausible, although such a
mechanism would require significant reorganization of com-
plex 8.
The optimized reaction conditions developed for the
enantioselective iodolactonization of 2a were applied to a
variety of other 5-substituted hexenoic acid derivatives
(Scheme 2). In the case of 5-arylhexenoic acids, a clear
correlation emerged between the electronic properties of the
arene and the observed ee, with electron-deficient derivatives
undergoing more enantioselective cyclization. For these less
4[d]
5
[a] Reactions performed on a 0.05 mmol scale. [b] Determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as the internal stan-
dard. [c] Determined by HPLC analysis using commercial chiral columns.
[d] Reaction performed using 2 equivalents of 5.
interesting to note that the absolute configuration of 10a was
found to be opposite to that of the hexenoic acid cyclization
products 3. The basis for the striking differences in behavior
between the pentenoic and hexenoic acid substrates is not
understood at this point, but is the subject of current analysis.
Another potentially valuable mechanistic clue is provided
by the fact that gem-dimethyl-substituted substrate 10b (R’ =
Me) was found to undergo cyclization to give racemic product
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toluene (8 mL) at ꢀ808C under a nitrogen atmosphere. After stirring
at this temperature for 5 days, the reaction mixture was quenched at
ꢀ808C by addition of 10% aqueous sodium thiosulfate solution
(4 mL) and partitioned between 1m sodium hydroxide solution
(30 mL) and CH2Cl2 (30 mL). The organic layer was separated,
further washed with 1m sodium hydroxide solution (30 mL), dried
(MgSO4), and concentrated in vacuum. Purification by flash column
chromatography on silica gel (5–40% ethyl acetate in hexanes)
afforded the iodolactone products.
Received: June 16, 2010
Published online: August 27, 2010
Keywords: anion binding · asymmetric catalysis · halogenation ·
.
iodolactonization · organocatalysis
[1] a) M. D. Dowle, D. I. Davies, Chem. Soc. Rev. 1979, 8, 171 – 197;
b) S. Ranganathan, K. M. Muraleedharan, N. K. Vaish, N.
Jayaraman, Tetrahedron 2004, 60, 5273 – 5308; c) A. N. French,
S. Bissmire, T. Wirth, Chem. Soc. Rev. 2004, 33, 354 – 362;
d) M. S. Laya, A. K. Banerjee, E. V. Cabrera, Curr. Org. Chem.
2009, 13, 720 – 730.
[2] Only two reports of moderately selective enantioselective
iodolactonization have appeared to date: a) M. Wang, L. X.
Gao, W. P. Mai, A. X. Xia, F. Wang, S. B. Zhang, J. Org. Chem.
2004, 69, 2874 – 2876; b) Z. L. Ning, R. H. Jin, J. Y. Ding, L. X.
Gao, Synlett 2009, 2291 – 2294.
[3] For examples of reagent-controlled enantioselective iodolacto-
nization see: a) O. Kitagawa, T. Hanano, K. Tanabe, M. Shiro, T.
Taguchi, J. Chem. Soc. Chem. Commun. 1992, 1005 – 1007;
b) R. B. Grossman, R. J. Trupp, Can. J. Chem. 1998, 76, 1233 –
1237; c) J. Haas, S. Piguel, T. Wirth, Org. Lett. 2002, 4, 297 – 300;
d) J. Haas, S. Bissmire, T. Wirth, Chem. Eur. J. 2005, 11, 5777 –
5785; e) J. M. Garnier, S. Robin, G. Rousseau, Eur. J. Org. Chem.
2007, 3281 – 3291.
Scheme 2. Substrate scope in the catalytic iodolactonization reaction.
Reactions were performed on a 0.2 mmol scale. Yields are of isolated
product following purification by column chromatography. Enantiomer-
ic excesses (ee) were determined by HPLC or GC (3e) analysis on
commercial chiral columns. See Supporting Information for full
details.
[4] For successful examples of other types of enantioselective
halocyclization reactions see: a) S. H. Kang, S. B. Lee, C. M.
Park, J. Am. Chem. Soc. 2003, 125, 15748 – 15749; b) A.
Sakakura, A. Ukai, K. Ishihara, Nature 2007, 445, 900 – 903;
c) D. C. Whitehead, R. Yousefi, A. Jaganathan, B. Borhan, J.
Am. Chem. Soc. 2010, 132, 3298 – 3300; d) W. Zhang, S. Q.
Zheng, N. Liu, J. B. Werness, I. A. Guzei, W. P. Tang, J. Am.
Chem. Soc. 2010, 132, 3664 – 3665.
under the conditions optimized for 9a. Analogous gem-
dimethyl substitution in the hexenoic acid case also led to
significant decrease in ee (product 3 f). In general, it was
found that any factors expected to lead to more rapid
cyclization of the iodonium ion intermediate (8, Scheme 1)
led to diminished enantioselectivities. If the rates of the two
steps (iodonium formation, 7!8 and cyclization, 8!9,
Scheme 1) are finely balanced, it is possible that acceleration
of the second step changes the identity of the rate- and ee-
determining step to formation of the iodonium ion. Poor face
selectivity in the iodination of the alkene would then be
responsible for the decreases in enantioselectivity.
In conclusion, under appropriate conditions, tertiary
aminourea derivative 1 induces enantioselective iodolactoni-
zation reactions to afford 5- and 6-membered iodolactones
with high levels of enantioselectivity. Studies to elucidate the
mechanism and origin of enantioinduction in this process are
underway.
[5] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713 –
5743; b) Z. G. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38,
1187 – 1198.
[6] a) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126,
10558 – 10559; b) I. T. Raheem, P. S. Thiara, E. A. Peterson,
E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404 – 13405;
c) S. C. Pan, B. List, Org. Lett. 2007, 9, 1149 – 1151; d) E. A.
Peterson, E. N. Jacobsen, Angew. Chem. 2009, 121, 6446 – 6449;
Angew. Chem. Int. Ed. 2009, 48, 6328 – 6331; e) R. R. Knowles, S.
Lin, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132, 5030 – 5032.
[7] a) R. S. Klausen, E. N. Jacobsen, Org. Lett. 2009, 11, 887 – 890;
b) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science
2010, 327, 986 – 990.
[8] C. K. De, E. G. Klauber, D. Seidel, J. Am. Chem. Soc. 2009, 131,
17060 – 17061.
[9] T. Mita, E. N. Jacobsen, Synlett 2009, 1680 – 1684.
[10] S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
2008, 130, 7198 – 7199.
Experimental Section
N-Iodo-4-fluorophthalimide (58 mg, 0.2 mmol) followed by iodine
(7.6 mg, 0.03 mmol) were added as solids to a stirred solution of the 5-
hexenoic acid (0.2 mmol) and catalyst 1 (15.4 mg, 0.03 mmol) in
[11] Details of the catalyst screen are provided in the Supporting
Information.
[12] V. K. Chaikovskii, A. A. Funk, V. D. Filiminov, T. V. Petrenko,
T. S. Kets, Russ. J. Org. Chem. 2008, 44, 935 – 938.
7334
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Chemie
[13] For full details of the optimization of the N-iodoimide see the
[16] M. Date, Y. Tamai, T. Hattori, H. Takayama, Y. Kamikubo, S.
Supporting Information.
[14] Complex 7 displays changes in the H NMR spectrum compa-
Miyano, J. Chem. Soc. Perkin Trans. 1 2001, 2001, 645 – 653.
[17] CCDC 781487 (3g) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
1
rable to those observed upon protonation of 1 with strong
mineral acids. See Supporting Information for further details.
[15] DFT calculations were performed using the hybrid GGA
functional B3PW91/6-31g(d) with a modified SDD pseudopo-
tential, as described in Ref. [3d].
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