Design and synthesis of Fmoc-SPPS-ready iodoarene amino acid pre-catalysts and their reactivity in the catalytic oxytosylation of ketones

Article abstract of DOI:10.1016/j.tetlet.2020.151723

A small suite of iodo-aryl amide containing amino acids were synthesized and assessed as catalysts for the hypervalent iodine(III) mediated α-oxytosylation of ketones. The efficiency of each catalyst was determined by comparing the relative rates of catalysis in the direct α-oxytosylation of propiophenone. In addition, these catalysts can be easily converted to congeners that are suitable for Fmoc-solid phase peptide synthesis for facile incorporation into a chiral peptide framework. This work facilitates the broader goal of our program to develop peptide-based enantioselective catalysts for hypervalent iodine chemistry.

Full text of DOI:10.1016/j.tetlet.2020.151723

Journal Pre-proofs
Design and Synthesis of Fmoc-SPPS-ready Iodoarene Amino Acid Pre-Cata-
lysts and their Reactivity in the Catalytic Oxytosylation of Ketones
Timothy R. Lex, Maria I. Swasy, Soham Panda, Beau R. Brummel, Lauren N.
Giambalvo, Kristopher G. Gross, Colin D. McMillen, Khadijatul Kobra,
William T. Pennington, Daniel C. Whitehead
PII:
S0040-4039(20)30146-5
DOI:
https://doi.org/10.1016/j.tetlet.2020.151723
TETL 151723
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 November 2019
3 February 2020
6 February 2020
Please cite this article as: Lex, T.R., Swasy, M.I., Panda, S., Brummel, B.R., Giambalvo, L.N., Gross, K.G.,
McMillen, C.D., Kobra, K., Pennington, W.T., Whitehead, D.C., Design and Synthesis of Fmoc-SPPS-ready
Iodoarene Amino Acid Pre-Catalysts and their Reactivity in the Catalytic Oxytosylation of Ketones, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151723
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Design and Synthesis of Fmoc-SPPS-ready Iodoarene Amino Acid Pre-Catalysts and their
Reactivity in the Catalytic Oxytosylation of Ketones
Timothy R. Lex, Maria I. Swasy, Soham Panda, Beau R. Brummel, Lauren N. Giambalvo,
Kristopher G. Gross, Colin D. McMillen, Khadijatul Kobra, William T. Pennington, Daniel C.
Whitehead*
Department of Chemistry, Clemson University, Clemson, SC, USA 29634
* Corresponding author. E-mail address: dwhiteh@clemson.edu (D.C. Whitehead).
Graphical Abstract:
Abstract: A small suite of iodo-aryl amide containing amino acids were synthesized and
assessed as catalysts for the hypervalent iodine(III) mediated -oxytosylation of ketones. The
efficiency of each catalyst was determined by comparing the relative rates of catalysis in the
direct α-oxytosylation of propiophenone. In addition, these catalysts can be easily converted to
congeners that are suitable for Fmoc-solid phase peptide synthesis for facile incorporation into
a chiral peptide framework. This work facilitates the broader goal of our program to develop
peptide-based enantioselective catalysts for hypervalent iodine chemistry.
1

Keywords: Hypervalent Iodine; Oxidation; Catalysis; Amino Acid
Introduction
In recent years, a number of chiral materials bearing aryl iodides have emerged as
versatile organocatalysts and reagents for enantioselective processes hinging on hypervalent
iodine(III) intermediates.1-4 The main attraction of utilizing hypervalent iodine catalysts arises
from their ability to act as practical alternatives to heavy metals due to their inexpensive cost,
environmentally benign and stable nature, and similar reactivity patterns in comparison to
transition metals.3-5 In the last decade, considerable attention has been focused on applying
catalytic amounts of chiral aryl iodide precatalysts or iodine (III) stoichiometric reagents for
enantioselective processes.2,5 Many groups have demonstrated success with such systems, yet
processes deploying highly modular and easily tunable catalyst scaffolds are less developed.6-9
A number of investigations have validated the use of chiral peptide scaffolds in
asymmetric catalysis.10-13 The utility of peptides as catalysts stems from their facile synthesis,
modular nature, and functional versatility.12-14 We have initiated a strategy to combine the
desirable features of hypervalent iodine(III) catalysis with the modularity of peptide scaffolds
with the ultimate goal of developing a new class of peptide-based precatalysts that might be
useful for enantioselective processes governed by hypervalent iodine(III) chemistry.
Initially, our group reported an investigation of the steric and electronic determinants
that govern the reactivity of iodoarene amide catalysts in the direct -oxytosylation of
propiophenone (Scheme 1, see catalysts 1-3 and generic peptide 4).15 In the context of our
broader catalyst design strategy, the study of N-butyl iodoarene amides 1-3 was motivated by a
2

desire to investigate the effects of the amide functional group on the catalytic performance of
aryl iodide precatalysts. This line of inquiry was pursued because the amide linkage
represented a logical means to incorporate the aryl iodo motif into a broader peptide
framework. Nevertheless, this strategy was necessarily limited to the installation of the aryl
iodo amide precatalyst to the N-terminus of the peptide chain (e.g. generic precatalyst 4) using
conventional Fmoc solid phase peptide synthesis (SPPS).16-18 While it was noted that the
presence of an amide moiety slightly impaired the rate of the transformation, three highly
reactive catalysts 1-3 emerged from this study, all of which positioned the iodine pre-catalyst
in the meta position relative to the amide.
In the next phase of our efforts, we envisioned the incorporation of similar, highly
reactive iodoarene amides into the side chain of Fmoc-SPPS-ready amino acids (i.e. generic
scaffolds 5 and 6, Scheme 1). Such a strategy would allow for the incorporation of the
iodoarene active site anywhere along the peptide sequence by means of routine SPPS (see
generic peptide 7). Herein, we report the straightforward synthesis of a series of Fmoc-
protected amino acids (6) that incorporate the critical iodoarene active site onto the amino acid
side chain via an amide bond. Further, we demonstrate that these iodoarene containing amino
Scheme 1. Strategies for incorporating highly reactive aryl-iodo amide precatalysts into a peptide
backbone for asymmetric hypervalent iodine catalysis.
3

acids exhibit comparable reactivity in the catalytic α-oxytosylation of ketones. Finally, we have
demonstrated the feasibility of incorporating these novel amino acids into a peptide scaffold by
means of conventional SPPS.
Results and Discussion
We elected to install the appropriate iodoarene active site onto the side-chain of
various diamino acids, through an amide coupling, resulting in a variety of iodinated amino acid
catalyst analogs (11a – 13d, Scheme 2). One would expect that the tether length between the
free amine, slated to bear the Ar-I(III) active site, and the amino acid -carbon might play a vital
role in the design of an effective chiral catalyst, therefore we elected to probe simultaneous
modification of L-diaminopropanoic acid (Dap, n = 1), L-diaminobutanoic acid (Dab, n = 2), L-
ornithine (Orn, n = 3) and L-lysine (Lys, n = 4). Our syntheses began with the commercially
available N-protected carboxybenzyl (i.e. Cbz or Z) diamino acids, because the Z protecting
group was more suitable for conventional amidation reaction conditions than the base-labile
Fmoc protecting group. Furthermore, we opted to first convert the N-Z-diamino acids to their
methyl ester derivatives in order to avoid undesirable side-reactions during the acylation step.
4

The synthetic route for our small series of N-Z-amino methyl ester I(III)-precatalysts 11a
– 13d is outlined in Scheme 2. To begin, the commercially available N-Z-diamino acids (8) were
converted to their corresponding acyl chlorides in the presence of thionyl chloride and then
reacted with methanol in order to generate the methyl esters, 9. The desired active iodoarene
sites (i.e. 10) were then coupled to the free amine side-chain following traditional base-assisted
amidation conditions to provide the desired iodo-arene amide containing amino acids 11a –
13d. Scaffold 12a was successfully characterized by by X-ray crystallography (Fig. 1).
Figure 1. X-ray structure of amino acid 12a.
5

Catalysts 11a – 13d (Scheme 2) were then investigated as catalysts for the -
oxytosylation of propiophenone (14). All conversion rates and enantioselectivities (i.e. % ee) of
product 15 were obtained by means of GC and chiral stationary phase HPLC analysis,
respectively. The direct α-oxytosylation of propiophenone 14 was initially carried out for 24 h
at room temperature in the presence of 10 mol % catalyst (Table 1).
6

Table 1. Evaluation of catalysts 11a – 13d for
the -oxytosylation of propiophenone (14).
N-Z-amino methyl ester I(III)-precatalysts 12b, 12c, 13b, and 13c generated the desired
-oxytosylated propiophenone product 15 in quantitative yields following the allotted 24 h
(Entries 6-7 and 10-11, Table 1). Precatalyst structures 12b and 12c represent a 5-iodo-2-
methoxy active site attached to the side-chain of Z-Dab-OMe and Z-Orn-OMe (12b, n = 2 and
12c, n = 3), respectively. Precatalysts 13b and 13c possess a 5-iodo-2-methoxy-4-methyl
7

iodoarene structure with amino acid side-chain lengths of n = 2 and 3. In order to discern the
identity of the most active catalyst(s) in our 24 h screen, reactions promoted by the four best
catalysts (12b, 12c, 13b, and 13c) were quenched with dimethylsulfide after only 4 h. As shown
in Table 2, catalyst 13c – containing the active iodoarene site on the side-chain of the methyl
ester derivative of ornithine – performed the best, followed by catalyst 12b, with a 2-carbon
tether length, providing the desired product in 49% and 46% conversions, respectively. (Entries
Table 2. Evaluation of catalysts 12b,c and 13b,c for
the -oxytosylation of propiophenone (14) over 4 h.
1 and 4, Table 2)
Catalysts 11a and 11d, with side chain tether lengths of n = 1 and n = 4, resulted in the
lowest yields after 24 h at room temperature, with n = 4 giving the desired product 15 in only
35% yield (Entries 1 and 4, Table 1). This data suggests that there may be an ideal intermediate
distance (in terms of catalyst activity) between the Ar-I site and the -carbon of the amino
methyl ester. Evidently, the most reactive catalytic framework involves the attachment of the
iodoarene two or three methylene units away from the amino -carbon. Conversely, the
8

presence of one or four methylene units (i.e. modified Z-Dap-OMe and Z-Lys-OMe) results in
slower conversion during the -oxytosylation of propiophenone.
Not surprisingly, there was no significant enantioinduction observed in the preparation
of 15 promoted by our library of functionalized amino methyl ester catalysts; they all resulted
in essentially racemic mixtures of the -oxytosylated product 15 regardless of side-chain tether
length or the active iodoarene constituent (Tables 1 and 2).
Next, we modified the Cbz-protected amino methyl ester 11a into an Fmoc-SPPS
compatible amino acid (16) in order to demonstrate that the iodo-arene amide containing
amino acids could be employed directly in solid phase peptide synthesis (Scheme 3). In order to
accomplish this task, the methyl ester in 11a was converted to the free carboxylic acid via
saponification, then the Cbz-protecting group of the diamino acid was removed in the presence
of trimethylsilyl iodide (TMSI).19, 20 Subsequently, the amine was re-protected with the base-
labile Fmoc carbamate.20-22 These amino acids are accessible at gram scale as demonstrated by
the preparation of Fmoc-SPPS-compatible amino acid catalyst 16 which contains an
unsubstituted iodoarene active site tethered one methylene away from the -amino acid
carbon.
Scheme 3. Conversion of 11a into Fmoc-SPPS ready 16 and incorporation
into -turn peptide 17.
9

Further, we were able to demonstrate the successful incorporation of 16 into a simple -turn
peptide with the sequence Ac-Ile-(16)-Pro-D-Ala-Ala-Ala (17) following standard Fmoc-SPPS
protocols.16-18 Briefly, the peptide was prepared on the Rink Amide MBHA resin that is
functionalized with an Fmoc-protected amine. Following resin swelling (CH2Cl2) and standard
Fmoc-deprotection (20% 4-methylpiperidine in DMF) the desired amino acid residues were
sequentially assembled onto the resin utilizing double treatments of HCTU as the coupling
agent in the presence of diisopropylethylamine in DMF.16 Upon coupling and deprotection of
the final N-terminal amino acid (i.e. Ile), the N-terminus was acetylated by treatment of the
resin with 5% acetic anhydride in DMF (5 mL, 5 min). The final iodoarene-containing peptide
(17) was cleaved from the resin and side-chain deprotected following standard trifluoroacetic
acid (TFA) cleavage conditions (TFA/H2O/triisopropylsilane, 95:4.5:0.5). Upon filtration from
the resin, evaporation of the cleavage cocktail, and precipitation with ice cold ether a powdery,
white peptide was obtained in 72% yield as judged from the resin loading. MALDI-TOF MS
analysis was used to verify the success of this synthesis (See ESI for full details).
Conclusion
In conclusion, we have successfully generated a series of modified diamino acids that
bear an iodoarene catalytic site (i.e. 11a – 13d) suitable for I(III) mediated transformations. We
have evaluated the reactivity of theses novel amino-acids in the context of the catalytic I(III)
mediated -oxytosylation of propiophenone. Further, these materials can be appropriately
protected for facile incorporation into a peptide sequence by means of conventional Fmoc-
SPPS. We hope to leverage these novel amino acids in the pursuit of developing an innovative
10

class of peptide-based iodoarene catalysts for asymmetric hypervalent iodine chemistry. The
results of these broader efforts will be reported in due course.
Author Information
Corresponding Author
*E-mail: dwhiteh@clemson.edu
Acknowledgments
This work was supported by the National Science Foundation (CHE-1664920) to D.C.W. This
work was also facilitated by a National Science Foundation Major Research Instrumentation
grant (CHE-1725919) for a 500 MHz Bruker NEO NMR spectrometer with a Prodigy (R)
cryoprobe. The authors are grateful to Mr. Daniel Steigerwald and Prof. Babak Borhan
(Michigan State University) for assistance with HRMS analyses.
References
1. Brenet, S.; Berthiol, F.; Einhorn, J. Eur. J. Org. Chem. 2013, 36, 8094-8096.
2. Parra, A.; Reboredo, S. Chem. Eur. J. 2013, 19, 17244−17260.
3. Hypervalent Iodine Chemistry – Modern Developments in Organic Synthesis; Wirth, T.,
Ed.; Springer: Berlin, 2003; Vol. 224.
4. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299-5358.
5. Liang, H.; Ciufolini, M. A. Angew. Chem. Int. Ed. 2011, 50, 11849 – 11851.
6. Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328−3435.
7. Brown, M.; Farid, U.; Wirth, T. Synlett 2013, 24, 424−431.
8. Parra, A.; Reboredo, S. Chem. - Eur. J. 2013, 19, 17244−17260.
9. Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.; Yamasaki, M.; Shiro, M.; Fujioka, H.;
Maruyama, A.; Kita, Y. J. Am. Chem. Soc. 2013, 135, 4558−4566.
11

10. Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610.
11. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726-3748.
12. Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481-2495.
13. Duschmale, J.; Arakawa, Y.; Wennemers, H. Asymmetric Organocatalysis 2012, 2, 741-
786.
14. Togo, H.; Sakuratani, K. Synlett, 2002, 1966−1975.
15. Lex, T. R.; Swasy, M. I.; Whitehead, D. C. J. Org. Chem. 2015, 80, 12234-12243.
16. Hood, C. A.; Fuentes, G.; Patel, H.; Page, K.; Menakuru, M.; Park, J. H. J. Pept. Sci. 2008,
14, 97-101.
17. Chan, W. C.; White, P. D. Fmoc Solid Phase Peptide Synthesis: A Practical Approach;
Oxford University Press: Oxford, UK, 2000.
18. Fields, G. B.; Noble, R. L. Int. J. Peptide Res. 1990, 35, 161-214.
19. Urwyler, S.; Floersheim, P.; Roy, B. L.; Koller, M. J. Med. Chem., 2009, 52, 5093–5107.
20. Wang, Y.; Bluhm, L. H.; Li, T. Anal. Chem., 2000, 72, 5459-5465.
21. Kretsinger, J. K.; Schneider, J. P. JACS. 2003, 125, 7907-7913.
22. Dzubeck, V.; Schneider, J. P. Tet. Lett. 2000, 41, 9953–9956.
12

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
13

Highlights:
-
-
A series of novel iodo-arene containing amino acids were prepared
The iodo-arene amino acids were evaluated as catalysts for the oxytosylation of
propiophenone
-
An iodo-arene amino acid was successfully incorporated into a hexapeptide by FMOC
SPPS.
14

Graphical Abstract:
15