Selective alkylation/oxidation of N-substituted isoindolinone derivatives: Synthesis of N-phthaloylated natural and unnatural α-amino acid analogues

Article abstract of DOI:10.1016/j.tetlet.2017.08.032

The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid intermediates is demonstrated by the preparation of several natural and unnatural α-amino acid derivatives using a two-carbon N-isoindolinone (phthalimidine) scaffold. Using a selective benzylic oxidation, the N-isoindolinone group is then converted to the N-phthaloyl group for convenient removal (65–98%). For preparation of the isoindolinone products which were to be the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-protected glycine equivalent on deprotonation to demonstrate the utility of the N-protected isoindolinone synthon (51–93%). While the ensuing benzylic oxidation is employed successfully for converting the N-isoindolinone group to the N-phthaloyl group in simple substrates, substrates bearing unsaturated or electron-rich side chains respond poorly to the oxidation.

Full text of DOI:10.1016/j.tetlet.2017.08.032

Accepted Manuscript
Selective alkylation/oxidation of N-substituted isoindolinone derivatives: syn-
thesis of N-phthaloylated natural and unnatural α-amino acid analogues
Pravin C. Patil, Frederick A. Luzzio, Jarrid M. Ronnebaum
PII:
S0040-4039(17)31028-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.032
TETL 49222
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 July 2017
11 August 2017
12 August 2017
Please cite this article as: Patil, P.C., Luzzio, F.A., Ronnebaum, J.M., Selective alkylation/oxidation of N-substituted
isoindolinone derivatives: synthesis of N-phthaloylated natural and unnatural α-amino acid analogues, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.032
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Selective alkylation/oxidation of N-
substituted isoindolinone derivatives:
synthesis of N-phthaloylated natural and
unnatural -amino acid analogues
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P. C. Patil, F. A. Luzzio*, J. M. Ronnebaum

Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Selective alkylation/oxidation of N-substituted isoindolinone derivatives: synthesis of
N-phthaloylated natural and unnatural -amino acid analogues
Pravin C. Patil , Frederick A. Luzzio and Jarrid M. Ronnebaum
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid
intermediates is demonstrated by the preparation of several natural and unnatural -amino acid
derivatives using a two-carbon N-isoindolinone (phthalimidine) scaffold. Using a selective
benzylic oxidation, the N-isoindolinone group is then converted to the N-phthaloyl group for
convenient removal (65-98%). For preparation of the isoindolinone products which were to be
the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-
protected glycine equivalent on deprotonation to demonstrate the utility of the N-protected
isoindolinone synthon (51-93%). While the ensuing benzylic oxidation is employed successfully
for converting the N-isoindolinone group to the N-phthaloyl group in simple substrates,
substrates bearing unsaturated or electron-rich side chains respond poorly to the oxidation.
Available online
Keywords:
Amino acids
Isoindolinones
Oxidation
Protecting Groups
Non-proteinogenic
1. Introduction
In multistep synthesis, it is possible for protecting groups to perform multiple roles by providing both orthogonal protection as well
as activation of neighboring atoms for further bond formation.1 A notable case in point is the development of the versatile
benzophenone imine (RN=CPh2, R=carboxymethylene) derivatives of glycine by O’Donnell and co-workers for the preparation of
diverse -amino acids.2 Thus, the two-carbon fragments having both the masked nitrogen and the ester functions falls into the category
of synthons termed “glycine equivalents.”3 The design and utilization of glycine equivalents allows for the de novo preparation of a
plethora of natural and unnatural amino acids.4 While the need for the de novo synthesis of natural α-amino acids most frequently
includes isotopic analogues, the requirement for unnatural or otherwise non-proteinogenic amino acids may stem from the areas of
protein engineering, drug design or enzyme modification.5 Nevertheless, many de novo syntheses require that the α-methylenes or
methines of glycine equivalents may be activated to give either anions or cations which then facilitate the attachment of the requisite
‘natural or unnatural’ side chains.6 While glycine equivalents typically bear both a protected nitrogen and carboxyl group with the -
methylene group available for C-C bond formation, one must note that protection of the nitrogen is not an absolute necessity-as
demonstrated by the chiral amino alcohol-derived glycinamide synthons developed by Myers and coworkers.7 When N or O
protection is warranted, the removal of these types of protecting groups is a distinct consideration and can be one or two-step processes.
If the requirements are multistep, the overall process typically renders the deprotection protocol easier when addressing the removal of a
particularly robust protecting group-i.e., those typically used for withstanding the more vigorous chemical reactions. While the N-
isoindolinone group is not a protecting group per se, the capability of converting it into the well-known N-phthaloyl group would place
it in that class of derivatives. We report herein that an adjoining N-isoindolinone group allows the -methylene of an ethyl- or a tert-
butyl ester to be deprotonated under basic conditions and facilitates the installation of side chains through the addition of reactive
electrophiles such as alkyl halides. After the installation of the new side chain, the N-isoindolinone group is then selectively oxidized to
the easily-removable N-phthaloyl group which is an established protecting group in peptide chemistry. We have reported that the
overall process involving the alkylation/N-isoindolinone-N-phthaloyl interconversion is effective for preparing ethynylalanine
derivatives en route to triazolylalanine analogues via click chemistry.8 More detailed studies are included in this Letter where we report
———
 Corresponding author. Tel.: +0-502-852-7323; fax: +0-502-852-8149; e-mail: faluzz01@louisville.edu

the scope of the alkylation reaction as well as details involving the response of selected substrates to the benzylic oxidation of the N-
isoindolinone moiety.
2. Results and Discussion
Our synthesis begins with the preparation of N-isoindolinone-derived esters 1 and 2 (Scheme 1).9 Generation of the sodium salt
of
isoindolinone
(NaH/THF)
followed by slow addition of either
bromoacetate afforded the N-
solid materials in yields of 78%
chromatography on silica gel. The
alkylation reactions involved base
mediated anion generation using
ethyl bromoacetate or tert-butyl
isoindolinonoyl esters 1 and 2 as
and 97% respectively after column
lithium
hexamethyl
disilazide
(LiHMDS) and entailed a fairly
standard protocol entailing addition
of LHMDS to a mixture of the
electrophile and ester 1 or 2 (Table
1). Under similar conditions, bases
such as potassium tert-butoxide,
sodium ethoxide and cesium
carbonate did not give promising
results. The usage of base was
critical
as
isoind
olinon
es can
suffer
deprot
onatio
n
of
the benzylic methylene,10 hence the possibility of multiple alkylated
products which result in complex mixtures. While the employment
of the ethyl ester 1 with reactive alkyl halides gave the expected
products in modest to good yields, less reactive alkyl halides gave
poor yields and what appeared to be decomposition of the starting
ester 1 during the course of the reaction. For purposes of clarity, we
organized the electrophiles and their products (3-13, Table 1) into
three groups. These included the alkyl iodides, affording products 3-
6 (70-86%), the allyl/propargyl bromides, giving products 7 and 8
(93, 78%, respectively), and finally the benzylic electrophiles which
provided the aromatic-derived products 9-13 (51-82%). For the
alkylation reactions, individual procedures for all compounds are presented in the Supplementary Data.
A number of reagents/conditions were evaluated for the benzylic oxidation of the lactam moiety of alkylation products 3-13 to the
corresponding N-phthaloyl derivatives 14-20 (Scheme 2).11 With attention to expense and ease of protocol, systems
such as MCPBA (m-chloroperbenzoic acid) and combinations of oxygen, or 2,2'-bipyridinium chlorochromate (BPCC)/MCPBA, SeO2,
Oxone®/KI were unreactive or gave complex mixtures. Finally, an optimal system composed of Oxone®/KBr in acetonitrile-water gave
the best results in benzylic oxidation thereby delivering the N-phthaloyl products 14-20 (Table 2).12 While substrate 2 (Table 2) is the
starting material for alkylation and is not an alkylation product per se, it does represent a ‘glycine equivalent’ and for purposes of
completeness it was included in the oxidations and gave the N-phthaloyl ester 14. It should be noted that the Oxone®/KBr system is the
first application of this type of oxidant to an isoindolinone to give the corresponding imide.8,11 While the benzylic oxidations to the
phthalimides appear to be a straightforward process, some examples were not
without
anomalous or unexpected results.

The failure of substrates 7, 8 and 11 to respond to the Oxone®/KBr
system may stem from the relatively electron-rich nature of the allyl,
propargyl and 4-methoxybenzyl side chains of these substrates. Using
optimized conditions, oxidation of the naphthylmethyl isoindolinone
derivative 12 did effect the expected conversion of the benzylic
methylene to the carbonyl, but with accompanying bromination on the
2-position of the naphthyl ring to afford the monobromo derivative 21
(80%) (Scheme 3). Using isoindolinone ethyl ester 1, LiHMDS and
2-bromomethyl-4,5-diphenyloxazole 23 as a co-reactant,13 the
expected
-
oxazol-2-
(methyl)-
substituted
derivative
was
yl-
13
isolated (63%, Table 1). Considering that the 2-substituted-4,5-
diphenyloxazole group is a masked carboxyl equivalent,14 the
alkylation reaction gave essentially the aspartate derivative 13 with
both carboxyl groups protected. Oxidation of 13 with Oxone®/KBr in
acetonitrile/water transformed the N-isoindolinone group into the N-
phthaloyl group, but also resulted in oxazole cleavage to give the N-
phthaloylasparagine
ester 22 (65%) (Scheme
3).
A straightforward
adaptation of the overall
method for peptide
chemistry is shown in
Scheme 4. The N-
phthaloyl phenylalanine
derivative
19
was
treated with hydrazine
hydrate (MeOH-H2O)
followed by direct
treatment with di-tert-
butyl dicarbonate (NaHCO3/dioxane). Thus, the racemic N-BOC
phenylalanine tert-butyl ester derivative 24 was obtained in 81% yield
over two steps whereby the spectral properties of the N-BOC amino
acid ester 24 matched those as previously reported (See
Supplementary Material).
In summary, the expedient of the N-isoindolinone group as a
nitrogen protecting group for a two carbon ‘glycine eqivalent’ is
demonstrated by submission of the scaffold to a series of selective
alkylation reactions. Removal of the N-isoindolinone group is
facilitated by conversion to the more labile N-phthaloyl group through
a selective benzylic oxidation using Oxone®. Using a diverse array of alkylating agents, the N-isoindolyl-protected ‘glycine equivalent’
served as a starting point for -amino acid construction and proved to be robust through further manipulation. An added bonus may be
the increased stability of the isoindolinone group to mildly acidic conditions as compared to the O’Donnell derivatives. While the
majority of isoindolinone substrates did afford the corresponding N-phthaloylated products upon oxidation, the vinylalanine-,
ethynylalanine- and electron-rich substrates such as methoxyphenylalanine analogues did not respond to oxidation. A noteworthy
example was the de novo preparation of the asparagine derivative 22 which resulted from both the benzylic oxidation and an oxazole
cleavage. While the isoindolinone core has been common to medicinal compounds,15 experimental therapeutics16 and natural products,17
its employment as a protecting group has received no attention. An asymmetric variant of the isoindolinone oxidation scheme is under
investigation and the results will be reported in due course.

Acknowledgments
The measurement of high and low resolution mass spectra by Dr. Michael Walla of the Mass Spectrometry Laboratory, Department
of Chemistry and Biochemistry, University of South Carolina is acknowledged. Financial support from the NIH/NIDCR through grant
1RO1DE023206 is gratefully acknowledged.
References and notes
1.
2.
Greene, T. W.: Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons: New York, 1999.
O’Donnell MJ, Bennett WD, Bruder WA, Jacobsen WN, Knuth K, LeClef B, Polt, RL, Bordwell FG, Mrozack SR, Cripe TA. J. Am. Chem. Soc.
1988; 110, 8520-8525.
3.
4.
Patek M. Int. J. Peptide Protein Res. 1993; 42: 97-117.
For selected reviews See: Noisier AFM, Brimble MA. Chem. Rev. 2014; 114: 8775-8806. Najera C, Sansano JM. Chem. Rev. 2007; 107: 4584-4671.
Kazmaier, U. In Amino Acids, Peptides and Proteins in Organic Chemistry; Hughes A. B, Ed; Wiley-VCH: Weinhein, 2009; pp 1-34.
(a) Saghyan AS, Langer P. Asymmetric Synthesis of Non-Proteinogenic Amino Acids; Wiley-VCH: Weinheim, 2016; P. 261. (b) Stevenazzi A,
Marchini M, Sandrone G, Vergani B, Lattanzio M. Biorg. Med. Chem Lett. 2014; 24: 5349-5356.
For an example of a ‘cationic glycine equivalent’ See: O’Donnell MJ, Delgado F, Drew MD, Pottorf RS, Zhou C, Scott WL. Tetrahedron Lett. 1999;
40: 5831-5835.
(a) Myers, AG, Gleason, JL,Yoon, T, Kung DW. J. Am. Chem. Soc. 1997; 119: 656-673. (b) Seiple IB, Mercer JAM, Sussman R J, Zhang Z, Myers
AG. Angew. Chem. Int. Ed. 2014; 53: 4642-4647.
Patil PC, Luzzio FA. Synlett 2017: DOI: 10.1055/s-0036-1588510; Art ID st-2017-b0340-c. In this report, the N-isoindolinone group was found to be
stable to the aqueous hydroxide conditions used to cleave the ester group of the alkylated amino acid scaffolds.
(a) Aubert T, Farnier M, Guilard R. Can. J. Chem. 1990; 68: 842-851. (b) Golec, G.; Charifson, P.; Charrier, J.-D.; Binch, H. US20030232846A1;
Chem. Abstr. 2003, 9917h.
5.
6.
7.
8.
9.
10. (a) Luzzio F A, Piatt Zacherl D. Tetrahedron Lett. 1998; 39: 2285-2288. (b) Couture A, Deniau E, Ionescu D, Grandclaudon P. Tetrahedron Lett.
1998; 39: 2319-2320.
11. (a) Luzzio FA In Science of Synthesis; Weinreb SM, Ed.; Georg Thieme: Stuttgart, 2005; Vol. 21, pp 301–303. (b) Luzzio FA, Zacherl DP, Figg WD,
Tetrahedron Lett. 1999; 40: 2087-2090.
12. Moriyama K, Takemura M, Togo H. Org. Lett. 2012; 14: 2414-2417.
13. Patil PC, Luzzio FA. Tetrahedron Lett. 2016; 57: 757-759.
14. Patil PC, Luzzio FA. Tetrahedron Lett. 2017; 58: 1280-1282.
15. Galustian C, Dalgleish A. Expert Opin. Pharmacother. 2009; 10: 125-133.
16. Riedinger C, Endicott JA, Kemp SJ, Smyth LA, Watson A, Valeur E, Golding BT, Griffin RJ, Hardcastle IR, Noble ME, McDonnell JM. J. Am.
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A. Supplementary Material
1
General procedures and supplementary data (FTIR, H NMR, 13C NMR) for compounds 1, 2, 3-13 and 14-22 and HRMS data for all
new compounds associated with this article can be found, in the online version, at http://dx.doi.org/j.tetlet,
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Highlights
Luzzio
TETL-D-17-01420-Revised
 A range of α–amino acid derivatives may be prepared depending on the alkyl halide.
 The N-isoindolinone protecting group is removed by a mild two-step sequence.
 Oxidation of the isoindolinone gives the easily-removable N-phthaloyl group.
 A de novo synthesis of an N-, carboxyl-protected arginine derivative was done.
 The oxidation method may be useful for 4,5-diphenyloxazole cleavage.