Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst

Article abstract of DOI:10.1021/ol3030555

The enantioselective iodolactonizations of a series of diversely substituted olefinic carboxylic acids are promoted by a BINOL-derived, bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the corresponding γ- and δ-lactones having stereogenic C-I bonds in excellent yields and >97:3 er. Significantly, this represents the first organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic resolutions of racemic unsaturated acids is also demonstrated.

Full text of DOI:10.1021/ol3030555

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Iodolactonization
of Disubstituted Olefinic Acids Using
a Bifunctional Catalyst
Chao Fang, Daniel H. Paull, J. Caleb Hethcox, Christopher R. Shugrue, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin,
Texas 78712, United States
sfmartin@mail.utexas.edu
Received November 6, 2012
ABSTRACT
The enantioselective iodolactonizations of a series of diversely substituted olefinic carboxylic acids are promoted by a BINOL-derived,
bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the
corresponding γ- and δ-lactones having stereogenic CꢀI bonds in excellent yields and >97:3 er. Significantly, this represents the first
organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic
resolutions of racemic unsaturated acids is also demonstrated.
Electrophilic halocyclizations of R,ω-functionalized al-
kenes represent an important class of reactions in organic
chemistry.1 In particular, halolactonizations of unsatu-
rated acids have been widely used in organic chemistry to
prepare intermediates in the synthesis of biologically active
natural products and other compounds having potential
utility.2 Given the importance of these cyclizations, there
has been considerable interest in developing enantioselec-
tive variants, and a number of notable advances in devel-
oping enantioselective bromolactonizations of unsaturated
acids 1 to give lactones 2 (X = Br, Figure 1) have been
recently reported.3 However, the corresponding catalytic,
enantioselective chloro-3f,4 and iodolactonizations5 to give 2
(X = Cl and I, Figure 1) are less common and much more
restrictive in substrate scope.
The first catalytic, enantioselective iodolactonization
was reported in 2004 by Gao, who used quaternary
ammonium salts derived from cinchonidine to promote
cyclizations of 5-aryl-4(E)-pentenoic acids. However, these
reactions proceeded with only moderate enantioselectivity,
and mixtures of γ- and δ-lactones were often obtained.5a
Gao and co-workers later found that a salen-Co(II)
complex catalyzed enantioselective iodolactonizations of
several 4-aryl-4-pentenoic acids to give γ-lactones with up
(1) For recent reviews, see: (a) Chen, G.; Ma, S. Angew. Chem., Int.
Ed. 2010, 49, 8306–8308. (b) Tan, C. K.; Zhou, L.; Yeung, Y. Synlett
2011, 1335–1339. (c) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.
Aldrichimica Acta 2011, 44, 27–40. (d) Denmark, S. E.; Kuester,
W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938–10953.
(2) (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171–197.
(b) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman,
N. Tetrahedron 2004, 60, 5273–5308. (c) Lava, M. S.; Banerjee, A. K.;
Cabrera, E. V. Curr. Org. Chem. 2009, 13, 720–730. (d) Rodriguez, F.;
Fananas, F. J. In Handbook of Cyclization Reactions;Ma, S., Ed.;Wiley-VCH:
New York, 2010; Vol. 4, pp 951ꢀ990.
(3) (a) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.;
Tang, W. J. Am. Chem. Soc. 2010, 132, 3664–3665. (b) Murai, K.;
Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka,
H. Angew. Chem., Int. Ed. 2010, 49, 9174–9177. (c) Zhou, L.; Tan, C. K.;
Jiang, X.; Chen, F.; Yeung, Y. J. Am. Chem. Soc. 2010, 132, 15474–
15476. (d) Tan, C. K.; Zhou, L.; Yeung, Y. Org. Lett. 2011, 13, 2738–
2741. (e) Tan, C. T.; Le, C.; Yeung, Y. Chem. Commun. 2012, 48, 5793–
5795. (f) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng,
S.; Werness, J. B.; Tang, W. Chem.;Eur. J. 2012, 18, 7296–7305.
(g) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.; Fujioka,
H. Chem.;Eur. J. 2012, 18, 8448–8453. (h) Jiang, X.; Tan, C. K.; Zhou,
L.; Yueng, Y. Angew. Chem., Int. Ed. 2012, 51, 7771–7775. (i) Paull,
D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J. Am.
Chem. Soc. 2012, 134, 11128–11131.
(4) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am.
Chem. Soc. 2010, 132, 3298–3300.
(5) (a) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.;
Zhang, S. B. J. Org. Chem. 2004, 69, 2874–2876. (b) Ning, Z.; Jin, R.;
Ding, J.; Gao, L. Synlett 2009, 2291–2294. (c) Veitch, G. E.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2010, 49, 7332–7335. (d) Dobish, M. C.;
Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068–6071. (e) Tungen,
J. E.; Nolsøe, J. M. J.; Hansen, T. V. Org. Lett. 2012, 14, 5884ꢀ5887.
r
10.1021/ol3030555
XXXX American Chemical Society

Table 1. Iodolactonization of 5-Substituted-4(Z)-Pentenoic Acidsa
entry
R
product
yieldb (%)
erc,d
Figure 1. Enantioselective halolactonizations.
a
i-Pr
i-Bu
6a
6b
6c
6d
6e
6f
93 (95)e
94
97.5:2.5
98:2
b
to 92:8 er.5b Veitch and Jacobsen recently discovered that
5-aryl-5-hexenoic acids undergo enantioselective iodolac-
tonizations, typically with >95:5 er, in the presence of a
tertiary aminourea catalyst.5c Most recently Dobish and
Johnston utilized a chiral Brønsted acid catalyst to pro-
mote enantioselective iodolactonizations of an extensive
series of 5-aryl-5-hexenoic acids, usually with >98:2 er.5d
Despite these achievements, there are a number of signifi-
cant limitations to existing methods. In particular, there
are few examples of iodolactonizations of olefinic acids
bearing alkyl groups on the double bond,5bꢀd and these
cyclizations invariably have occurred with lower enantios-
electivity than their aryl counterparts. Moreover, there
are no examples of iodolactonizations that generate new
CꢀI bonds at stereogenic centers. Because the products
of such cyclizations may bear two new stereocenters,
existing iodolactonization methods are not applicable to
the direct synthesis of compounds containing multiple
stereocenters.
We envisioned that these and other gaps in prevailing
methods might be addressed by adapting our recently
reported protocol for enantioselective bromolactoniza-
tions that are catalyzed by 3.3i In particular, we queried
whether 4, which is formed quantitatively in situ by
bromination of 3 under conditions used for bromolacto-
nization, might promote highly enantioselective iodolac-
tonizations. We thus discovered that 4 catalyzed the
iodolactonizations of various disubstituted olefinic acids
with N-iodosuccinimide (NIS) to deliver iodolactones in
excellent yields and enantioselectivities.6 To our knowledge,
this is the first instance where the same organocatalyst is
highly effective for both bromo- and iodolactonizations.
Herein we report the details of some of our findings.
We found that both 5-alkyl-4(Z)-pentenoic acids 5aꢀd
and 5-aryl-4(Z)-pentenoic acids 5eꢀh undergo iodolac-
tonization in the presence of 4 (10 mol %) and NIS
(1.2 equiv) at ꢀ20 °C to furnish the γ-lactones 6aꢀh as the
only isolable products in >97:3 er and in excellent yield
(Table1, entries aꢀh). The reactionwith5awas alsoran on
0.5 mmol scale to give the iodolactone product 6a in 95%
yield and 97.5:2.5 er (Table 1, entry a). These cycliza-
tions proceed via an exo mode of ring closure with high
c
t-Bu
99
97:3
d
c-Hex
97
98:2
ef
f
Ph
93
98.5:1.5
99:1
p-NC-C6H4
p-Cl-C6H4
2-Np
95
gg
hh
6g
6h
89
98:2
94
98:2
a Reactions run on 0.1 mmol scale. b Isolated yield after column
chromatography. c er determined by chiral HPLC. d Absolute stereo-
chemistry of 6c and 6e established by X-ray analysis; 6aꢀb,d,fꢀh were
based on analogy. e Yield in parentheses obtained on 0.5 mmol scale.
f Z/E ratio of 5e, 20:1. g Z/E ratio of 5g, 11:1. h Z/E ratio of 5h, 17:1.
regioselectivity to generate products with two contiguous
stereogenic centers. Diastereomeric products were ob-
served only when the starting Z-alkene contained detect-
able amounts of the inseparable E-isomer. The presence of
electron-withdrawing groups on the aromatic ring is well
tolerated, but the products obtained from substrates hav-
ing electron-rich aromatic rings, such as p-methoxyphenyl,
are unstable and suffer extensive decomposition dur-
ing isolation and purification. In the reactions of cis-aryl
olefinic acids 5eꢀh, no products arising from a 6-endo
cyclization pathway were observed. We tentatively attri-
bute this observation to the difficulty of achieving the
planar arrangement in the transition state necessary for
maximum stabilization of the developing positivechargeat
the benzylic position.7
The utility of organocatalyst 4 is further exemplified by
the enantioselective iodolactonizations of 6-aryl- and 6-al-
kyl-5(Z)-hexenoic acids such as 7aꢀd to provide the
corresponding δ-lactones 8aꢀd in high yields and up to
99:1 er (Table 2). No regioisomeric products were ob-
served, and diastereomeric products were detected only if
the starting Z-alkene contained discernible amounts of
E-isomer. Although an electron-withdrawing group slo-
wed the iodolactonization reaction, the selectivity was not
adversely affected (Table 2, entry b).
In contrast to the high enantioselectivities observed
for 5-substituted-4(Z)-pentenoic acids 5aꢀh, iodolac-
tonizations of 5-alkyl-4(E)-pentenoic acids are some-
what less selective, as exemplified by the cycliza-
tion of 9a to give 10a (Table 3, entry a). The divergent
levels of enantioselectivity in the iodolactonizations of
(6) In preliminary experiments, we found that iodolactonizations
catalyzed by 4 were slightly faster and/or higher yielding than those
promoted by 3; both catalysts can be recovered, unmodified, from
iodolactonization reactions.
(7) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330–5334. (b) Nicolaou, K. C.;
Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989,
111, 5335–5340.
B
Org. Lett., Vol. XX, No. XX, XXXX

an electron-withdrawing group favors iodolactonization by
an exo mode of closure that is not very enantioselective
(Table 3, entry d).
Table 2. Iodolactonization of 6-Substituted-5(Z)-Hexenoic Acidsa
Catalytic enantioselective transformations may be
applied to kinetic resolutions, which can provide an
enantiomerically pure product from a racemic starting
material. There are, however, fewer examples of such
processes with organic catalysts than with metal or
enzyme catalysts. Although there is a recent report of
a kinetic resolution of a racemic, unsaturated acid by
bromolactonization,9 we are aware of no example of a
kinetic resolution by an iodolactonization. It is thus
notable that 4 promotes the kinetic resolution of com-
mercially available 2-cyclopentene-1-acetic acid (12) to
give bicyclic iodolactone (þ)ꢀ13 in 44% yield (88% of
theoretical) in 83:17 er (eq 1).10 Compound (þ)-13 and
its enantiomer are important intermediates in the
syntheses of a number of targets.11
entry
R
product
yieldb (%)
erc,d
ae
bf,g
cg
d
Ph
p-NC-C6H4
2-Np
8a
8b
8c
8d
89
88
93
98
99:1
99:1
98.5:1.5
98:2
t-Bu
a Reactions run on 0.1 mmol scale. b Isolated yield after column
chromatography. c er determined by chiral HPLC. d Absolute stereo-
chemistry of 8aꢀd are based on analogy with 6c and 6e. e Z/E ratio of 7a,
14:1. f Z/E ratio of 7b, 20:1. g Results obtained after 38 h at ꢀ20 °C.
Table 3. Regiochemistry in Iodolactonization of 5-Substituted-
4(E)-Pentenoic Acidsa
As mentioned previously, halolactones are useful inter-
mediates for the synthesis of a number of other com-
pounds. One important application of their utility is
exemplified by their conversion into epoxides. Although
there are some excellent methods for the enantioselective
synthesis of epoxides,12 there remain some gaps inmethods
for preparing epoxides having certain substitution pat-
terns. For example, enantioselective epoxidation of uncon-
jugated, cis-1,2-dialkyl alkenes lacking suitable directing
groups is not well-documented.13 It is thus significant that
treatment of 6d with Cs2CO3 in MeOH afforded the corre-
sponding epoxy ester 14 in 87% yield with essentially com-
plete retention of enantiopurity (eq 2). Application of this
iodolactonizationꢀepoxidation sequence therefore provides
a practical approach to the enantioselective synthesis of cis-
epoxides that were heretofore not accessible.
entry
R
product
yieldb (%)
erc,d
a
i-Pr
Ph
10a
10bþ11b
11c
78
89e
89
94
67:33
52:48(95:5)f
86.5:13.5
58:42
b
c
dg
p-MeO-C6H4
p-NC-C6H4
10d
a Reactions run on 0.1 mmol scale. b Isolated yield after column
chromatography. c er determined by chiral HPLC. d Absolute stereo-
chemistry of iodolactones was assigned based on analogy with corre-
sponding bromolactone analogs.3i e Combined yield; ratio of 1.3:1.0 based
upon NMR analysis. f Er shown in parentheses is for 11b. g Reaction
performed for 14 h at ꢀ20 °C and 48 h at ꢀ10 °C in CH2Cl2/tol (1:1).
5-alkyl-4(E)- and 5-alkyl-4(Z)-pentenoic acids mirror the
related bromolactonizations,3i which may reflect a prefer-
ential side-on approach of the olefin during formation of
the iodonium ion in analogy with known enantioselective
epoxidations of olefins.8 The iodolactonization of 9b was
not regioselective, giving an inseparable mixture (1.3:1.0)
of the γ- and δ-lactones 10b and 11b via 5-exo and 6-endo
cyclization pathways, respectively (Table 3, entry b). For
other 5-aryl-4(E)-pentenoic acids, we find, like Gao,5a that
the electronic nature of substituents on the aromatic ring
has a marked effect upon the regioselectivity of the iodo-
lactonization (Table 3, entries c,d). For example, 9c under-
goes both regio- and enantioselective iodolactonization
preferentially via an endo mode of ring closure (6-endo/
5-exo > 20:1) to give 11c with 86.5:13.5 er. The presence of
In summary, we have discovered that the BINOL-
derived catalyst 4 is a useful bifunctional catalyst for pro-
moting the highly enantioselective iodolactonizations of a
wide array of olefinic acids. Moreover, to our knowledge 4
isthe first organocatalystthatiscapableof promoting both
highly enantioselective bromo- and iodolactonizations.
The iodolactonizations of 5-substituted-4(Z)-pentenoic
(9) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.;
Hamashima, Y.; Kan, T. Org. Lett. 2012, 14, 6016ꢀ6019.
€
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Chem. 2003, 2122–2127.
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€
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Org. Lett., Vol. XX, No. XX, XXXX
C

and 6-substituted-5(Z)-hexenoic acids typically proceed
with >97:3 er to give the corresponding γ- and δ-lactones
having two contiguous stereogenic centers. Indeed, these
reactions represent the first examples where new CꢀI
bonds are formed with high enantioselectivity by iodolac-
tonizations. The potential of 4 and analogs thereof for
effecting enantioselective syntheses of iodolactones by
kinetic resolution is also demonstrated. Moreover, the
product lactones can be converted into epoxides, thereby
enabling the highly enantioselective preparation of certain
substituted epoxides that were heretofore inaccessible. The
utility of 4 and related catalysts to promote highly enan-
tioselective reactions as key steps in natural product
synthesis is under active investigation as are studies to
elucidate the mechanism and the origin of stereoinduction
in these cyclizations.
(12) For reviews and leading references, see: (a) Johnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-CVH: New York, 2000; pp 231ꢀ280. (b) Jacobsen, E. N.; Wu,
M. H. In Comprehensive Asymmetric Catalysis, 1st ed.; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, pp
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Y. Acc. Chem. Res. 2004, 37, 488–496. (e) Yang, D. Acc. Chem. Res.
2004, 37, 497–505. (f) Denmark, S. E.; Wu, Z. Synlett 1999, 847–859.
(g) Shibasaki, M.; Kanai, M.; Matsunaga, S. Aldrichachim. Acta 2006,
39, 31–39. (h) Zhang, F.-Y.; Corey, E. J. Org. Lett. 1999, 1, 1287–1290.
(i) Page, P. C. B.; Buckley, N. R.; Blacker, A. J. Org. Lett. 2004, 6, 1543–
1546. (j) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 6964–6965. (k) Lee, S.; MacMillan,
D. W. C. Tetrahedron 2006, 62, 11413–11424.
Acknowledgment. We thank the National Institutes of
Health (GM31077) and the Robert A. Welch Foundation
(F-0652) for generous support of this research. D.H.P.
thanks the NIH for a postdoctoral fellowship (GM 96557).
We are also grateful to Dr. Vincent Lynch (The University
of Texas) for X-ray crystallography.
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds, and X-ray
crystal data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Recently Shi reported a modified fructose-derived ketone to
promote enantioselective epoxidation of limited scope of cis-olefins with
good enantioselectivity: Burke, C. P.; Shi, Y. Org. Lett. 2009, 11, 5150–
5153.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX