A peptide bromoiodinane approach for asymmetric bromolactonization

Article abstract of DOI:10.1016/j.tetlet.2011.02.056

A series of 37 peptides containing an iodo-aryl amide active site were generated by means of both solid phase and conventional synthesis. These peptides were screened for asymmetric induction in the bromolactonization of 4-phenyl-4-pentenoic acid based on the generation of chiral bromoiodinane bromenium sources. The study culminated in the discovery of a tri-peptide iodo-aryl amide that effected the desired bromolactonization in quantitative conversion with 24% ee. The experiments disclosed herein provided valuable insight that ultimately facilitated the development of more synthetically useful enantioselective halocyclization methodology.

Full text of DOI:10.1016/j.tetlet.2011.02.056

Tetrahedron Letters 52 (2011) 2288–2291
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A peptide bromoiodinane approach for asymmetric bromolactonization
⇑
Daniel C. Whitehead, Matthew Fhaner, Babak Borhan
Department of Chemistry, Michigan State Univerisity, East Lansing, MI 48824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 37 peptides containing an iodo-aryl amide active site were generated by means of both solid
phase and conventional synthesis. These peptides were screened for asymmetric induction in the bromol-
actonization of 4-phenyl-4-pentenoic acid based on the generation of chiral bromoiodinane bromenium
sources. The study culminated in the discovery of a tri-peptide iodo-aryl amide that effected the desired
bromolactonization in quantitative conversion with 24% ee. The experiments disclosed herein provided
valuable insight that ultimately facilitated the development of more synthetically useful enantioselective
halocyclization methodology.
Received 9 December 2010
Revised 12 February 2011
Accepted 14 February 2011
Available online 26 February 2011
Keywords:
Bromolactonization
Organocatalysis
Asymmetric
Ó 2011 Elsevier Ltd. All rights reserved.
Peptides
Bromoiodinane
The development of asymmetric halocyclizations hinging on the
selective delivery of a halenium source (X+) onto an olefin sub-
strate is currently a burgeoning area of research in asymmetric
catalysis.1 Although transformations of this type have traditionally
yielded only marginal selectivities,2 select examples of asymmetric
olefin halogenation reactions that proceed in high enantioselectiv-
ity have only recently begun to emerge. Ishihara and co-workers
recently disclosed an elegant methodology for effecting highly
enantioselective polyene cyclizations based on the formation of a
chiral iodonium intermediate employing a chiral phosphoramidite
promotor.3 The Kang laboratory has developed an asymmetric iod-
oetherification protocol mediated by a catalytic loading of a chiral
Co-salen complex.4 Recently, the Snyder group featured a unique,
highly enantioselective olefin chlorination as the key step in the to-
tal synthesis of Napyradiomycin A1.5
We disclosed a related enantioselective chlorolactonization
protocol in early 2010 (Eq. 1).6 This methodology allows for the
enantioselective chlorolactonization of 4-arylpentenoic acids by
the action of 1–10 mol % of (DHQD)2PHAL and 1,3-dichloro-5,5-
diphenylhydantoin (DCDPH, 3) as the terminal chlorenium source.
The desired chiral chlorolactones are returned in good yield with
enantioselectivities ranging from 72% ee to 90% ee. Contemporary
with our report several elegant, highly selective asymmetric bro-
mo7 and iodolactonization8 protocols have appeared in the litera-
ture. Very recently, we have extended our protocol to include the
highly enantioselective chlorocyclization of allylic amides to gen-
erate chiral oxazolines and dihydrooxazines.9
A different approach to the problem has been our efforts in
developing peptide-based chiral catalysts to promote halolacton-
izations. We drew inspiration from a work disclosed by Braddock
and co-workers in 2009, whereby ortho-substituted aryl-iodo
amides and amidines (e.g., 6, Eq. 2) were able to significantly accel-
erate the NBS-mediated bromolactonization of various alkenoic
acids by the formation of I(III) bromoiodinane intermediates such
as 7.10 We envisioned rendering the process enantioselective by
incorporating an aryl iodo amide active site motif into a chiral pep-
tide framework. Disclosed herein is a full account of our efforts in
this regard, which culminated in the development of a peptide-
based catalyst library that returned the desired bromolactone
product with selectivities up to 24% ee.
O
Cl
N
(DHQD)2PHAL (0.1 equiv)
O
DCDPH ( ) (1.1 equiv)
3
O
OH
O
Ar
Ph
Ph
ð1Þ
Benzoic Acid (1 equiv)
CHCl3:Hex (1:1), -40 ºC
N
Cl
Ar
O
Cl
1
2
, 72-90% ee
3
NBS (1.2 equiv)
Br
OH
O
O
iodo-aryl-amide 6 (0.1 equiv)
O
CDCl3 RT, 0.5 h
5
, 100% conv.
4
ð2Þ
Br
O
Ι
O
Ι
Initially, we targeted three peptide-based scaffolds that incor-
porated the ortho-iodo aryl amide precatalyst motif (Scheme 1).
Linear scaffold 8 was loosely based on the linear peptidic scaffolds
popularized by Hoveyda and Snapper.11 The b-turn scaffold 10
made use of the well known Pro-D-Aaa turn motif.12 Peptides con-
taining the b-turn motif have been successfully employed as li-
gands13 and organocatalysts.14 Both of these scaffolds were
NBu
NHBu
6
7
⇑
Corresponding author.
E-mail address: babak@chemistry.msu.edu (B. Borhan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.056

D. C. Whitehead et al. / Tetrahedron Letters 52 (2011) 2288–2291
2289
readily available by means of a well-established Fmoc Solid Phase
Peptide Synthesis (SPPS).15 While scaffold 8 and 10 only allowed
for the incorporation of the o-iodo-amide active site at the N-ter-
minus of the peptide chain, scaffold 9 allowed for the incorporation
of the crucial active site within the heart of the peptide chain.
Although not readily available by SPPS, scaffold 9 was easily acces-
sible by conventional synthesis. Scaffold 9 vaguely resembles bis-
amino acid pyridine scaffolds that have been applied previously
for chiral recognition16 and catalysis17 applications.
We arrived at 4-phenyl-4-pentenoic acid 11 as a test substrate
owing to the fact that it was readily prepared in quantity from
commercially available methyl 3-benzoylpropionate by sequential
Wittig olefination and saponification (see Supplementary data).
tional Fmoc SPPS (except 47–50) and characterized by MALDI-
TOF mass spectrometry (see Supplementary data for details).
Catalysts 13–21 were screened at a 10 mol % loading in the test
transformation of 11 to bromolactone 12 in dichloromethane at
room temperature (Scheme 1, dashed box). In all cases, the desired
bromolactone was generated in complete conversion as indicated
by TLC.
Peptide 13 incorporated an aromatic side chain, while peptides
14, 15, and 16 incorporated various aliphatic side chains of increas-
ing steric bulk. Peptides 17–21 incorporated a basic residue on the
C-terminus separated from the aryliodo active site by a phenylala-
nine residue. The basic residues in these catalysts were incorpo-
rated in the hopes that they might serve to either deprotonate
and thus activate the carboxylic acid nucleophile or to coordinate
and thus orient the substrate in proximity with the active aryliodo
site. While most of the series were completely unselective, peptide
16 returned 12 in 7% ee. Given that this result was reproducible, 16
was taken to be an initial ‘hit’ scaffold, and subsequent efforts cen-
tered around the iterative optimization of that scaffold.
Based on scaffold 16, a second library of 10 peptides were pre-
pared by modulating the C-terminal amino acid distal to the aryl
iodoamide moiety. This residue was targeted for optimization
based on the assumption that the proximal tert-leucine residue
in 16 would be a crucial structural element for the selectivity that
was initially observed. Catalysts 23–32 (see substructure 22, Fig. 1)
were screened in the test reaction. While none of the peptides from
our second generation directed library out-performed the parent
scaffold 16, it is interesting to note some of the structural changes
that result in reduced selectivity. Simply put, it appears that both
tert-leucine residues housed in 16 are necessary to maintain the
observed 7% ee. Modulating the C-terminal residue to benzyl
(23), phenyl (24), basic (25), acidic (26), or carbinol (27) side chains
proved to be detrimental. More interesting still are the changes ob-
served by modulating the C-terminal tert-leucine to other aliphatic
side chains. Incorporating unbranched aliphatic chains (28) or
removing the site of branching farther away from the peptide
backbone (29) resulted in inferior catalysts. Even those catalysts
that maintained branching at the 1-position on the side chain
(30 and 31) were less selective. Finally, incorporating a methyl
group at the 3-position on the aryl iodoamide residue (32) resulted
in a poorly selective catalyst.
Having established that both tert-leucine residues in 16 were
necessary for the observed 7% ee, a longer analogue was prepared,
thus incorporating a third tert-leucine moiety. When screened in
the test reaction, tri-peptide 33 (see substructure 22) proved to
be twice as selective as its shorter cousin 16, retuning 12 in 14%
ee (peptide 33). After this result, a battery of experiments were
undertaken in an effort to enhance the selectivity of the transfor-
mation mediated by 33, by systematically optimizing the reaction
conditions. These efforts are disclosed in detail in the Supplemen-
tary data and include a solvent and temperature screen (Table S1),
a moisture inclusion/preclusion study (Table S2), catalyst equiva-
lency study (Table S3), concentration study (Table S4), and a scan
of 15 alternate bromine sources (Table S5). Unfortunately these
extensive efforts failed to improve upon the initially observed
selectivity of 14% ee.
Compound 11 is readily converted to the desired c-bromolactone
12 under racemic organocatalytic conditions with 10 mol % ortho-
iodobenzoic acid and NBS as reported by Braddock and cowork-
ers.10 The enantiomers of 12 are conveniently separated by chiral
HPLC (Chiralcel OD-H). In addition to these operational conve-
niences, the choice of compound 11 was also driven by the fact
that, at the time, some of the most recent attempts at the develop-
ment of an asymmetric reagent-controlled halolactonization reac-
tion focused on the 4-aryl-4-pentenoic acid substrate class.2d,g It
seemed that initially targeting this substrate class would provide
a convenient standard to which we might benchmark our progress.
Furthermore, the lactonization of this class of alkenoic acids pro-
ceeds cleanly to provide the c-lactone as the sole product without
undergoing competing d-lactone formation.
With regards to the scale of the screening protocol, we elected
to perform reactions in microscale, screening the peptides for the
asymmetric bromolactonization on a 0.05 mmol scale with respect
to substrate 11 (9 mg loading). This approach was taken in order to
facilitate a high-throughput screening approach. On this scale,
product purification could be carried out by performing silica gel
chromatography using packed Pastuer pipettes.
Additionally, this scale allowed for the judicious application of
only a few milligrams of the relatively more precious and expen-
sive peptide catalysts. The trade-off for such a small scale ap-
proach, however, was that tracking isolated yields on the scale of
a few milligrams was untenable. As a result, we chose to optimize
the catalyst scaffold and reaction conditions based upon the per-
turbations observed for the enantioselectivity of the transforma-
tion as the sole variable. Nonetheless, it warrants emphasis that
all of the transformations described in this manuscript proceeded
to completion as judged by TLC analysis prior to work-up.
Our initial efforts focused on the evaluation of scaffold 8. Fig-
ure 1 depicts the structures of the catalysts prepared in this study.
Peptides 13–21 represent our initial pilot library based upon scaf-
fold 8. All of the peptides in Figure 1 were prepared by conven-
Having sufficiently exhausted reasonable means for optimizing
the reaction conditions with catalyst 33, we again returned to the
generation of a third focused library in an attempt to improve the
selectivity of the transformation. A series of eleven new peptides
were prepared (Fig. 1, 34–44 Ar = ortho-iodophenyl). Peptides
34–36 were developed in order to determine if all three amino
acids in the peptide chain of 33 necessarily needed to be tert-leu-
cine residues to maintain selectivity. Peptides were, therefore, con-
structed whereby the amino acids in the peptide were sequentially
replaced with valine residues starting at the C-terminus (34) and
Scheme 1. Aryl-iodo peptide scaffolds and test reaction for asymmetric induction.

2290
D. C. Whitehead et al. / Tetrahedron Letters 52 (2011) 2288–2291
Figure 1. Aryl-iodo peptide catalysts for the asymmetric bromolactonization of 11.
moving toward the N-terminus (35 and 36). Peptide 37 was con-
structed to probe the necessity of the C-terminal amide. Peptides
38 and 39 were assembled to evaluate the consequences of
increasing the length of the peptide by the installation of a fourth
amino acid residue on the C-terminus. Catalysts 40 and 41 were
designed to evaluate the course of the reaction using a catalyst
with even bulkier residues than those found in 33. In this case
tert-butyl threonine units were installed in lieu of the tert-butyl
group resident in 33. Simultaneously, 42 was prepared to provide
the fully deprotected amide variant of 40. Finally, 43 and 44 were
assembled to probe the effects of installing an intervening proline
residue between the o-iodoarylamide active site and the tert-leu-
cine residues.
Peptides 34–44 were screened in the test transformation (11
and 12); the results are collected in Figure 1. As the C-terminal res-
idues were sequentially modulated from tert-leucine to valine, a
definite decline in selectivity was realized. While changing the C-
terminal tert-leucine farthest removed from the iodoarylamido ac-
tive site was tolerated (cf. 13% ee for 34 vs. 14% ee for 33), further
changes closer to the N-terminus of the scaffold resulted in poorly
selective catalysts (peptides 35 and 36). Switching all of the tert-
leucine moieties with valine resulted in a completely unselective
catalyst (36) while retaining only one tert-leucine (35) returned
the lactone in 7% ee. These data are in excellent agreement with
the initial experiments that lead to the discovery of 16 as a lead
scaffold, and serve to confirm the assertion that two flanking
tert-leucine residues represent a minimal structural element for
stereoinduction. Modulating the C-terminal amide in 34 to a C-ter-
minal carboxylic acid (37) had no effect on the selectivity of the
bromolactonization (peptides 34 and 37). On incorporating a
fourth amino acid residue (valine) on the C-terminus, a negligible
increase to 15% ee was realized with peptide 38. The failure of pep-
tide 38 to significantly improve upon the selectivity of 33 indicated
that extending the peptide length by incorporating further resi-
dues would likely be fruitless. Peptide 39 again confirms the neces-
sity of the two tert-leucine residues proximal to the iodoarylamido
site (2% ee). Further increasing the steric bulk of the catalyst by
incorporating tert-butyl threonine residues in lieu of tert-leucine
resulted in inferior catalysts (peptides 40 and 41). Similarly the
unprotected threonine analogue 42 was completely unselective.
The incorporation of a proline residue in between the iodoarylam-
ido active site and the crucial neighboring tert-leucine produced
peptides 43 and 44, which were inferior to the second generation
catalyst 33. These experiments further underscore the necessity
for the two tert-leucine residues neighboring the active site aryl-
iodoamido moiety as a minimal scaffold for a selective peptide.
In addition to the series of peptides generated about the gener-
alized scaffold 8, we also briefly investigated alternate scaffolds
including b-turn scaffold 10 and bis-amino acid scaffold 9. In that
vein, b-turn peptides 45 and 46 were prepared by standard SPPS
and screened in the test reaction for the enantioselective prepara-
tion of 12. While peptide 45 was completely unselective, peptide
46 returned lactone 12 in 5% ee. Perhaps a positional scanning re-
gime originating from 46 would eventually yield a useful catalyst,

D. C. Whitehead et al. / Tetrahedron Letters 52 (2011) 2288–2291
2291
actonization, as well as the design of new, rigidified, chiral cata-
lysts with a more defined asymmetric pocket is ongoing.
.
.
Acknowledgments
The authors thank Dr. Chrysoula Vasileiou and Dr. Kin-Sing Lee
for performing MALDI-TOF analysis. We thank the ACS PRF (No.
47272-AC, and the NSF (CHE-0957462) for generous funding.
.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.056.
Scheme 2. Stoichiometric asymmetric bromolactonization mediated 33.
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