Reagent-controlled stereoselective iodolactonizations

Article abstract of DOI:10.1021/ol0171113

Chemical equation presented Iodocyclizations are important transformations and among stereocontrolled iodocyclizations mostly substrate-controlled versions using a chiral auxiliary have been successfully investigated. This work reports on stereoselective

Full text of DOI:10.1021/ol0171113

ORGANIC
LETTERS
2002
Vol. 4, No. 2
297-300
Reagent-Controlled Stereoselective
Iodolactonizations
,†,‡
Ju1rgen Haas,†,‡ Sandrine Piguel,‡ and Thomas Wirth*
Department of Chemistry, Cardiff UniVersity, P.O. Box 912, Cardiff CF10 3TB, U.K.,
and Institute of Organic Chemistry, UniVersity of Basel, Switzerland
wirth@cf.ac.uk
Received November 23, 2001
ABSTRACT
Iodocyclizations are important transformations and among stereocontrolled iodocyclizations mostly substrate-controlled versions using a
chiral auxiliary have been successfully investigated. This work reports on stereoselective reagent-controlled iodolactonizations applying a
new method using a combination of ICl and a primary amine leading to the highest selectivities known so far.
Halocyclizations have been studied extensively, and this type
of transformation serves as an important key reaction in a
variety of syntheses.1 The first examples of this reaction
were described early in the last century,2 and the reaction
conditions developed at that time (aqueous solvent, base,
iodine) are still widely used.
This is also true for many substrate-controlled stereo-
selective iodocyclizations, where an existing chiral moiety
in the substrate controls the outcome of the reaction. This
type of control has been investigated in detail3 and applied
to natural product syntheses4 and to reactions on solid
support.5
Trupp described a dihydroquinidine-iodine complex as the
source of I+ in a chiral environment,6 while Brown and Cui
investigated cyclizations of 4-penten-1-ol using pyridines as
chiral ligands for Br+.7 The selectivities in the halolactones
synthesized did not exceed an enantiomeric ratio (er) of
57:43. Chiral electrophilic fluorination reagents have been
explored and have already been used in asymmetric synthe-
sis.8
Prior to the work reported herein, we had previously
prepared analogues of bis-(sym)-collidine-iodine-per-
chlorate (BCIP) for iodolactonizations.9 In that work sym-
collidine was replaced by a pyridine with a chiral moiety
attached to the 2-position. This strategy was similar to that
of Brown;7 hence we could not obtain enantiomeric ratios
exceeding 52:48.9
To our knowledge there are only two reports on reagent-
controlled stereoselective halolactonizations.6,7 Grossman and
† Cardiff University.
In reactions using BCIP, only one collidine molecule is
coordinated to the I+ during the addition step to alkenes.10
Consequently, the second collidine ligand has to dissociate
off before the reaction can take place. Additionally, it is
known that the complex of ICl and pyridine is linear with
one ICl molecule coordinated to the nitrogen atom.11
Therefore, first experiments were performed using an
equimolar ratio of I+ and amine in the reactions.
‡ University of Basel.
(1) (a) Dowle, M. D.; Davies, D. I. Chem. Soc. ReV. 1979, 171. (b)
Harding, K. E.; Tiner, T. H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 363. (c)
Mulzer, J. In Organic Synthesis Highlights; Mulzer, J., Altenbach, H. J.,
Braun, M., Krohn, K., Reissig, H. U., Eds.; VCH: Weinheim, 1991; p 157.
(d) Rousseau, G.; Robin, S. Tetrahedron 1998, 54, 13681.
(2) (a) Stobbe, H. Liebigs Ann. Chem. 1902, 321, 119. (b) Fittig, R.
Liebigs Ann. Chem. 1904, 331, 142. (c) Bougault, M. J. Ann. Chim. Phys.
1908, 14, 145.
(3) (a) Bartlett, P. A.; Richardson, D. P.; Myerson, J. Tetrahedron 1984,
40, 2317. (b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321. (c)
Hoffmann, R. W.; Stu¨rmer, R.; Harms, K. Tetrahedron Lett. 1994, 35, 6263.
(4) (a) Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc.
1980, 102, 2120. (b) Takano, S.; Murakata, C.; Imamura, Y.; Tamura, N.;
Ogasawara, K. Heterocycles 1981, 16, 1291. (c) Shi, Y.; Peng, L. F.; Kishi,
Y. J. Org. Chem. 1997, 62, 5666.
(6) Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233.
(7) Brown, R. S.; Cui, X. L. J. Org. Chem. 2000, 65, 5653.
(8) Mun˜iz, K. Angew. Chem. 2001, 113, 1701; Angew. Chem., Int. Ed.
2001, 40, 1653.
(9) Haas, J. Diploma Thesis, University of Basel, 1999.
(10) Brown, R. S.; Neverov, A. A. J. Org. Chem. 1998, 63, 5977.
(11) Hassel, O.; Rømming, C. Acta Chem. Scand. 1956, 10, 696.
(5) Moon, H.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1992, 57, 6088.
10.1021/ol0171113 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/20/2001

We chose the iodolactonization of 1 to 2 as a first model
reaction, because 2 contains only one stereogenic center and
the analysis of the product is straightforward (Scheme 1).12
Scheme 1. Stereoselective Lactonization Using ICl
A common side reaction of iodocyclizations, a subsequent
HI elimination, is impossible in molecules of type 2, because
the -CH2I moiety is adjacent to a quaternary carbon atom.
To investigate conditions and possible chiral ligands for
I+, initial experiments included a variety of enantiomerically
pure compounds such as carboxylic acids, alcohols, amino
alcohols, or amino acids. Only by using primary amines was
the iodolactone 2 obtained with some enantiomeric excess,
especially using ligands similar to (R)-1-phenylethylamine
3.13
Figure 1. Primary amines used as ligands in the iodolactonization
of 1 to 2.
We investigated I2, IBr, and N-iodosuccinimide (NIS) as
well as ICl as sources of I+, whereas ICl proved to be the
most efficient one. We therefore chose ICl as a convenient
reagent because the highest selectivities have been obtained
using this source of I+ (Table 1). The ratio of I+ and amine
Figure 1 shows a selection of primary amines which were
investigated as ligands. A variety of secondary and tertiary
amines showed only very small selectivities in the reaction
of 1 to 2.15
During the optimization studies, it was found that after
mixing the amine with ICl in CH2Cl2 it is essential to stir at
room temperature for 30 min to form the most selective
species (if this time exceeds 2 h, no reaction was observed).
After the mixture was cooled to -78 °C, a solution of 1
was added. The lactonization of 1 is very fast; NMR
investigations indicated a time scale below 2 min for the
formation of 2 at -60 °C. The yields of the iodolactoniza-
tions described are typically around 80%.16 Many screening
experiments have, however, only been performed on an
analytical scale without determination of yields. Further
investigations to gain more insight on the structure of the
Table 1. Iodolactonization of 1 Using Amine 3 as a Chiral
Ligand to ICl
source of I+
2 er (S:R)
NIS
I2
IBr
ICl
50:50
53.5:46.5
54:46
62.5:37.5
1
was optimized during the first experiments, and all subse-
quent experiments mentioned below are performed with a
ratio of 1:2 (ICl:amine).
reactive species were done by H NMR. The amine 3 was
titrated with ICl, and the results imply the formation of a
1:1 complex17 similar to published investigations.10 Ad-
Clearly, all the reactions decribed in Table 1 generate the
same absolute configuration in 2 with different selectivities
depending on the source of I+.14 Further optimization of the
reaction conditions was then carried out by investigating
temperature effects and solvent dependency as described
below.
(15) Secondary and tertiary amines used as ligands in the iodolacton-
ization of 1: (R)-1-(1-phenylethyl)pyrrolidine (2: 52.5:47.5 S:R), (R,R)-
N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine (2: er 50:
50), sparteine (2: er 50:50), sparteinesulfate (2: er 50:50), (S)-1,1′-
binaphthalenyl-2,2′-diamine (2: er 50:50), (S)-glutamic acid (2: er 50:50),
(R,R)-N,N′-1,2-cyclohexanediylbis(4-methyl-benzenesulfonamide) (2: er 50:
50), (S)-alaninol (2: er 50:50); the ratio of these amines to I+ was 1:1,
because of the minor selectivities observed they have not been repeated
using optimized conditions.
(16) A 1 M solution of ICl in CH2Cl2 (0.58 mmol, 0.58 mL) was added
dropwise to a solution of 6 (1.15 mmol, 169 mg) in CH2Cl2 (10 mL) at
room temperature. The resulting orange solution was stirred for 30 min
before cooling to -78 °C. A solution of 1 (0.28 mmol, 49 mg) in CH2Cl2
(3 mL) was then added. The reaction mixture was stirred for 15 min at
-78 °C before quenching with 10% aqueous Na2S2O3. After extraction
with CH2Cl2 (2 × 40 mL) the combined organic layers were washed with
brine and dried (MgSO4). Removal of the solvent in vacuo and purification
by column chromatography on silica (pentane:methyl-tert-butyl ether 2:1)
afforded 69 mg of (R)-2 (0.23 mmol, 82%) with an er of 27.5:72.5.
(17) The quadruplett of the benzylic proton in 3 was shifted to a higher
field, up to a ratio of 1:1, then to lower field.
(12) Spectroscopic data for 2. 1H NMR (300 MHz, CDCl3): δ ) 2.44-
2.82 (m, 4H), 3.63 (s, 2H), 7.35-7.41 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ ) 16.3, 29.2, 33.9, 86.0, 124.8, 128.6, 128.8, 140.6, 175.2. MS
(EI, 70 eV): m/z (%) 302 (1), 175 (46), 161 (100), 133 (8), 105 (38), 91
(34), 77 (22), 51 (13). The enantiomeric excess was determined by HPLC
(hexane:2-propanol ) 9:1). Chiralcel OD: 0.5 mL min-1; 270 nm; Rf(S) )
37.6 min; Rf(R) ) 43.0 min.
(13) R)-N-Methyl-1-phenylethylamine and (R)-N,N-dimethyl-1-phenyl-
ethylamine are much less efficient (2: er 51.5:48.5 and 50:50, respectively).
(14) The absolute configuration of 2 was determined by comparison of
the optical rotation after radical deiodination of 2 to the known 5-methyl-
5-phenyl-dihydrofuran-2-one: Albinati, A.; Bravo, P.; Ganazzoli, F.;
Resnati, G.; Viani, F. J. Chem. Soc., Perkin Trans. 1 1986, 1405.
298
Org. Lett., Vol. 4, No. 2, 2002

Table 2. Results of the Stereoselective Iodolactonization Using
Different Primary Amines as Ligands
Table 3. Solvent Dependency of the Stereoselective
Iodolactonization to 2 (-78 °C, ICl, 2 equiv of Amine)
amine
2 er (S:R)
amine
2 er (S:R)
2 er (S:R)
2 er (S:R)
solvent
(using amine 3)
(using amine 6)
3
4
5
6
7
8
9
10
62.5:37.5
35:65
41:59
27.5:72.5
45:55
51.5:48.5
37:63
12
13
14
15
16
17
18
19
20
54.5:45.5
40.5:59.5
57:43
57:43
57:43
50:50
50:50
52.5:47.5
51.5:48.5
Et2O
53:47
52.5:47.5
53:47
57.5:42.5
62.5:37.5
51.5:48.5
50:50
47.5:52.5
35:65
42.5:57.5
27.5:72.5
43.5:56.5
CH3CN
a
C6H6
CHCl3
CH2Cl2
CCl4
62:38
53:47
a Reaction performed at room temperature.
11
11‚HCl
50:50
The influence of the substrate on the selectivity of the
iodolactonization was then investigated by a series of
different substituted unsaturated carboxylic acids of type 21.
ditional UV experiments signify the formation of a 1:1
complex as well.18 Further experiments are needed to clarify
whether the active chiral electrophilic species is an amine:
ICl complex or an amine:I+ complex with Cl- already
dissociated from the complex.
Table 2 shows that amines with a structure similar to that
of 3 result in better selectivities than others. Substitution of
the aromatic moiety of 3 as well as altering the size of the
anellated ring (5, 6, 7) have been investigated. It can be seen
that substitution at the 4-position of the aromatic ring (10-
12) results in a smaller enantiomeric ratio in 2. An anellated
five-membered (5) or seven-membered ring (7) also resulted
in a decrease of the enantiomeric excess. In case of amine
hydrochlorides (e.g., 11‚HCl) racemic iodolactone 2 was
obtained independent of the amine. The ferrocene moiety in
13 did not enhance the selectivity.
Compounds 21 have been synthesized by Suzuki reac-
tions19 using 4-bromo-4-pentenoic acid ethyl ester20 and
appropriate boronic acids and subsequent basic cleavage of
the ethyl ester. The different acids and the iodolactonizations
leading to compounds 22 are shown in Scheme 2.
Scheme 2. Stereoselective Lactonization of Substituted
Carboxylic Acid Derivatives 21
Interestingly, a substituent in ortho-position to the chiral
amino moiety is changing the absolute configuration of
iodolactone 2. With amine 3, iodolactone (S)-2 is generated,
whereas iodolactone (R)-2 is obtained using amine 4 or the
amines 5, 6, or 7 with an anellated aliphatic ring system. A
study on skeletal alterations of 3 revealed that using (S)-
1,2,2-triphenylethylamine 19 with two phenyl groups at the
2-position or (S)-1,1-diphenyl-2-aminopropane 20 did result
in significantly lower selectivities (er (S:R) 52.5:47.5 and
51.5:48.5, respectively).
Obviously an aromatic moiety in the amine is not
necessary (14) to induce a stereoselective iodolactonization,
although the selectivity is lower than that using aromatic
amines.
From the results described in Table 4 it is obvious that
electron-withdrawing substituents at the 4-position of the
aromatic moiety lead to an increase in selectivity. The
intermediate iodonium ion is less stabilized and more
reactive. This finding can be rationalized with an altered
We then investigated the effect of the solvent and have
used the most successful ligand 6 as well as amine 3. A small
selection of different solvents is shown in Table 3.
Whereas all solvents led to the formation of product 2,
we found that methylene chloride gave the highest selectivity
in the iodolactonization of 1. Another promising solvent was
benzene at room temperature, leading to an er of 35:65 of 2
compared to 27.5:72.5 of 2 in methylene chloride at -78
°C. Mixtures of benzene and methylene chloride did not lead
to higher selectivities.
Table 4. Substituted Carboxylic Acids 21 in Iodolactonization
Reactions
acid
22 er
26:74
25.5:74.5
27.5:72.5
29.5:70.5
acid
22 er
21a
21b
1
21d
21e
21f
21g
36.5:63.5
45:55
50:50
(18) The formation of a 1:1 complex was found by generating a Job
plot by continuous variation of concentration. (a) Job, P. Ann. Chem. 1928,
9, 113. (b) MacCarthy, P. Anal. Chem. 1978, 50, 2165.
21c
50:50
Org. Lett., Vol. 4, No. 2, 2002
299

geometry of the intermediate iodonium ion formed,21 which
obviously affects the orientation of the chiral reagent and
influences the selectivity. Unsaturated carboxylic acids with
an aliphatic substituent (21f, 21g) only led to racemic
iodolactone in the cyclization reactions.
Scheme 3. Chiral Amides 23 and 24 in Substrate-Controlled
Iodocyclizations
Finally, we prepared the unsaturated chiral amides 23 and
24 (Scheme 3). Using these compounds in substrate-
controlled iodocyclizations, we could demonstrate that the
induction is smaller (er 55.5:44.5 and 65:35, respectively,
of (S)-2) than using the reagent complex ICl:amine described
above. It is interesting to see the opposite absolute config-
uration in iodolactone 2 synthesized from 1 using 6 as a chiral
ligand (Table 2, amine 6) and from amide 23 using the same
amine as a chiral auxiliary.
In conclusion, we have developed a new protocol for
reagent-controlled stereoselective iodolactonizations. This
method uses commercially available primary amines as the
chiral source together with ICl as a powerful source of I+.
The nature of the reactive complex and further studies to
optimize the reaction are in progress.
Acknowledgment. We thank Prof. Olaf G. Wiest (Uni-
versity of Notre Dame) and Martin Spichty (University of
Basel, Switzerland) for discussing theoretical aspects of this
project and the Swiss National Foundation for financial
support.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
(19) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Littke,
A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(20) Gilchrist, T. L.; Kemmitt, P. D.; Germain, A. L. Tetrahedron 1997,
53, 4447.
(21) De La Mare, P. B. D. In Electrophilic Halogenation; Cambridge
University Press: Cambridge, 1976.
OL0171113
300
Org. Lett., Vol. 4, No. 2, 2002